Hindawi

Oxidative Medicine and Cellular Longevity

Volume 2017, Article ID 8495160, 16 pages
https://doi.org/10.1155/2017/8495160

Review Article
The Interrelation between Reactive Oxygen Species and
Autophagy in Neurological Disorders

Congcong Fang,1 Lijuan Gu,2 Daniel Smerin,3 Shanping Mao,1 and Xiaoxing Xiong2
1
Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China
2
Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China
3
Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA 94305-5117, USA

Correspondence should be addressed to Shanping Mao; [email protected] and Xiaoxing Xiong; [email protected]

Received 27 July 2017; Accepted 30 October 2017; Published 17 December 2017

Academic Editor: Eva Žerovnik

Copyright © 2017 Congcong Fang et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Neurological function deficits due to cerebral ischemia or neurodegenerative diseases such as Alzheimer’s disease (AD) and
Parkinson’s disease (PD) have long been considered a thorny issue in clinical treatment. Recovery after neurologic impairment
is fairly limited, which poses a major threat to health and quality of life. Accumulating evidences support that ROS and
autophagy are both implicated in the onset and development of neurological disorders. Notably, oxidative stress triggered by
excess of ROS not only puts the brain in a vulnerable state but also enhances the virulence of other pathogenic factors, just like
mitochondrial dysfunction, which is described as the culprit of nerve cell damage. Nevertheless, autophagy is proposed as a
subtle cellular defense mode against destructive stimulus by timely removal of damaged and cytotoxic substance. Emerging
evidence suggests that the interplay of ROS and autophagy may establish a determinant role in the modulation of neuronal
homeostasis. However, the underlying regulatory mechanisms are still largely unexplored. This review sets out to afford an
overview of the crosstalk between ROS and autophagy and discusses relevant molecular mechanisms in cerebral ischemia, AD,
and PD, so as to provide new insights into promising therapeutic targets for the abovementioned neurological conditions.

1. Introduction with the occurrence and development of cerebral ischemia

and neurodegenerative diseases [5].
Reactive oxygen species (ROS), an umbrella term for a cate- Autophagy is a precisely regulated biological process
gory of active oxygen-containing compounds generated from characteristic of eukaryotic cells during which the superflu-
aerobic metabolism [1], encompasses superoxide anion ous and damaged structures of cells are eliminated via lyso-
(O2−), hydrogen peroxide (H2O2), and free radical (superox- some degradation to maintain normal cellular physiological
ide and hydroxyl radicals). Each of these compounds can functions [6] for the purpose of adapting to all kinds of
damage biomacromolecules essential for various cellular pro- adverse stimuli. Existing studies suggest that autophagy is
cesses [2], while simultaneously playing an indispensable role widely engaged in neuronal fate determination in diverse
in the redox signaling cascade required for critically impor- neurological conditions [7–9]. However, excessive autophagy
tant biological events [3]. ROS are likely to cause oxidative can promote a programmed cell death, known as autophagic
stress when the oxidation of ROS outweighs the antioxida- cell death or type II programmed cell death [10], which is
tion [4], which is believed to damage cells. Compared with morphologically distinct from apoptosis and necrosis. That
other organs, the brain has the most active oxidative metab- is to say, moderate or optimal activation of autophagy is
olism, with a high demand for oxygen. The brain’s active desirable, and neither excessive nor insufficient autophagy
oxidative metabolism combined with its deactivation of completely lacks toxicity to neurons [11].
detoxification systems and severe deficiency of antioxidants ROS are associated with cell damage [12] and have tradi-
jointly upsets the redox balance, causing immeasurable oxi- tionally been thought to function solely as unfriendly mole-
dative brain tissue injury. This process is closely correlated cules, despite exposure to ROS being unavoidable for cells
2 Oxidative Medicine and Cellular Longevity

in an aerobic environment [13]. However, an increasing antioxidative systems that consist of enzymatic and nonenzy-
number of researchers have found that ROS can participate matic antioxidants. The former is represented by SOD, CAT,
in various physiological processes as a kind of signaling mol- and GSH-Px, while the latter includes glutathione (GSH),
ecule, including the induction of autophagy that is consid- vitamin C, vitamin E, and so forth. Nevertheless, when there
ered to be an effective defense mechanism against cellular exists any redox imbalance between the generation and the
stress [14, 15]. More importantly, it is the mitochondrial scavenging of ROS, oxidative stress occurs, leading to unpre-
ROS which is a master inducer of autophagy under condi- dictable oxidative damage to organelles, proteins, lipids, and
tions of nutrient starvation, ischemia, or hypoxia [16–18]. DNA, as well as the disruption of cellular structures and
Conversely, activation of autophagy is a key part of the cellu- functions and eventually cell death [25] (Figure 1).
lar response to oxidative stress because the process disposes
defective components before further damage/aggregation 2.2. Biomarkers of ROS/Oxidative Stress. Due to the nature of
occurs [19]. In summary, the interaction and the balance ROS, which are active for a relatively short lifespan, various
between ROS and autophagy can be a key part of regulating complex and time-consuming detection means such as elec-
cellular homeostasis. tron spin resonance and spin trapping technology are rela-
It is well established that both ROS and autophagy are tively difficult to practically implement, and the results are
strongly associated with neurological diseases, but clarifying also often offset by the mixing of heterogeneous groups
the functional relationship of the two mechanisms seems to [26]. Therefore, ROS or oxidative stress level is usually mea-
be difficult because of their dual role in many disease pro- sured by monitoring the activity of cellular antioxidant
cesses. This review is designed to state the role of ROS and enzymes such as SOD and GSH-px, each of which can indi-
autophagy in neurological disorders and their underlying rectly reflect the ability to remove ROS [27]. Concurrently,
molecular mechanisms so as to offer novel strategies for the GSH and malondialdehyde (MDA) are used to mirror oxida-
treatment of nervous system diseases. tive stress resistance and injury.
Superoxide dismutase, a copper-containing protein iso-
2. Reactive Oxygen Species (ROS) lated from bovine red blood cells by Mann et al. for the
first time in 1938, was rediscovered and named as SOD by
2.1. Generation and Scavenging of ROS. It is now well docu- Fridovich and Mccord in 1969. SOD is able to scavenge
mented that mitochondria are the main source of intracellu- ROS. The glutathione peroxide (GSH-Px) is extensively pres-
lar ROS; 90% of which are derived from the respiratory chain ent in the cytoplasm. Mitochondria contain two kinds of
on the mitochondrial inner membrane. The generation of GSH-Px, GSH-Px1 and GSH-Px4, by which lipid peroxide
mitochondrial ROS is initiated by the formation of O2− via induced by OH− can be decomposed into the corresponding
the combination of electrons leaking from the mitochondrial alcohol or peroxide-induced injury can be reduced [28]. As is
respiratory chain complexes (mainly complexes I and III) widely known, common ROS involved in cellular damage are
and O2. Highly active O2− can then be transformed into more mainly OH−, H2O2, and O2− [29]. The dynamic conversion
stable H2O2 in the presence of superoxide dismutase (SOD). among the three parts depends upon SOD and GSH-Px, only
The quick conversion of H2O2 into H2O can be catalyzed by by which can O2− be reduced into H2O, thus mitigating
catalase (CAT) and glutathione peroxidase (GSH-Px) and oxidation damage [30]. In conclusion, the activity of these
serves as the source of OH− as well [3, 20, 21]. two antioxidant enzymes may be the reflex of the ability to
Under normal circumstances, ROS emissions in mito- eliminate ROS [31] (Figure 1).
chondria are rather low and render minimal damage because Glutathione (GSH) is the most abundant nonprotein
mitochondria have potent antioxidant defense systems that thiol and broad-spectrum antioxidant in mitochondria
sufficiently scavenge unneeded ROS. Whereas, unbridled and contains two forms: reduced glutathione (GSH) and
ROS ensue only if mitochondria are subjected to deleterious oxidized glutathione (GSSG). The former accounts for
incidents while simultaneously experiencing a drop in trans- about 95% of GSH and, as the primary ROS scavenger,
membrane potential. There is a positive-feedback mechanism can effectively remove H2O2 and O2− and other free radi-
called “ROS-induced ROS release” (RIRR) that accounts for cals, while concurrently being transformed into recyclable
the interaction between ROS and mitochondria. During GSSG via glutathione reductase.
RIRR, a burst of mitochondrial ROS is evoked by ROS, reduc- In the above processes, catalase (CAT) and glutathione
ing mitochondrial membrane potential (MMP) and causing a reductase (GR) are typically used in combination with
longer opening of mitochondrial permeability transition SOD, GSH-Px, and GSH as potential antioxidant biomarkers
pores (mPTP) [22]. Generally, moderate activation of mPTP to evaluate oxidative stress.
is required for healthy mitochondrial metabolism. Once There are also some other ROS measurement parameters
mitochondria are attacked by an inappropriate release of based on oxidation of lipids, proteins, and DNA. Some
ROS, mitochondrial membrane depolarization interferes examples of these parameters are MDA, 4-hydroxy-2-
with mitochondrial respiratory chain function and can create nonenal (4-HNE), 3-nitrotyrosine (3-NT), and 8-OHdG.
a vicious circle provoking further ROS accumulation [23]. Any accumulation of oxidation byproducts implies deterio-
As mentioned, abnormally high levels of ROS can be ration through oxidative damage, but different byproducts
quickly neutralized to cellular levels by a complex network represent the different levels of cellular damage. Excess
of various robust antioxidants, which is essential for sustain- ROS inflict irreversible damage to nucleic acids, which
ing the normal functions of cells [24]. There are two major has been reported to be an early event in oxidative damage.
Oxidative Medicine and Cellular Longevity 3

Figure 1: The generation and scavenging of reactive oxygen species (ROS) in mitochondria. The “→” refers to activation or induction, and
the “⊢” refers to inhibition. Under normal or stress conditions, ROS is mainly born from the mitochondrial respiratory chain with the
beginning of O2− production, followed by the conversion to H2O2 then OH− under the catalysis of SOD and GSH-px. Defective
mitochondria can instigate ROS accumulation with a “RIRR” positive-feedback mechanism. Excessive ROS can inflict severe damage on
biomacromolecules, which can be counteracted by the antioxidant enzyme system to some degree.

8-Hydroxy-2′-deoxyguanosine (8-OHdG) is a biological Likewise 3-nitrotyrosine (3-NT), an important metabo-

index generated by the oxidation of DNA along with the lite of oxidative lesions in protein, has been measured in
loss of its integrity. As a pivotal biomarker of endogenous brain tissue, with increased levels in PD and AD popula-
oxidative DNA, 8-OHdG levels have been commonly tions. 3-NT is stable both in vitro and in vivo. There is a
assessed to estimate ROS-induced DNA lesions in multiple lot of value in the assessment of oxidative stress for clinical
neurological disorders. research [34].
As for malondialdehyde (MDA), the ubiquitous final
product of lipid peroxidation created by ROS attacking 2.3. ROS/Oxidative Stress-Related Signal Pathway. Keap1/
unsaturated fatty acids of biological membranes [32], its Nrf2/ARE cascades have proven to be the most important anti-
accumulation can incur cross-linking polymerization of oxidant defense, and almost all protective antioxidant genes
macromolecules such as protein and nucleic acid, perme- contain antioxidant response elements (ARE). When exposed
ability and destruction of membrane structures, and eventu- to oxidative stress, Keap1 (kelch-like ECH-associated protein
ally cell death. The degree of lipid peroxidation can be 1) can be separated from Nrf2 (nuclear factor erythroid 2-
estimated by the quantity of MDA in the tissue, so MDA related factor 2) by uncoupling activity or reduction of ubi-
is proposed to be one of the indicators of intracellular oxida- quitination and degradation, then translocation of Nrf2 into
tive stress [33]. Similarly, 4-hydroxy-2-nonenal (4-HNE), a the nucleus targeting ARE. Nuclear translocation leads to
specific clinical detection index of polyunsaturated fatty the expression of antioxidants and phase II detoxifying
acid peroxidation, is also currently utilized to measure the enzymes, which is shown to greatly reduce ROS and ensuing
extent of oxidative lipid damage. Isoprostane is the best oxidative damage.
available index of lipid peroxidation because of its stability. In addition, several intracellular signaling pathways
In summary, these indicators may better assess oxidative related to redox state, such as PI3K/Akt, JNK, MAPK, and
damage of brain tissue because various polyunsaturated ERK, can dissociate Nrf2 from Keap1 through phosphoryla-
fatty acids are susceptible to ROS during oxidative metabo- tion of Nrf2. These signaling pathways also cause Nrf2 to
lism in the brain. translocate to the nuclease and activate the antioxidant
4 Oxidative Medicine and Cellular Longevity

system, which is expected to augment the oxidative defense as a clinical parameter of oxidative damage in PD individuals.
capacity [35, 36]. Reactive (OH) and subsequent MDAs have been reported to
be significantly increased in PD patients, which contribute to
2.4. Reactive Oxygen Species (ROS) in Neurological Disorders. dopaminergic neuronal loss [50]. Nrf2 exists in the nigral
Loss of neurons is a key link in the pathophysiological pro- dopaminergic neuron cytoplasm, but is located in the nucleus
cess of nervous system diseases, which is mediated by oxida- of age-matched PD patients, which strongly suggests that
tive stress, mitochondrial disturbances, abnormal protein Nrf2 may contribute to combating oxidative brain damage
aggregation, and so on [37]. One of the most important prob- via the transcription of genes encoding antioxidant enzymes
lems is oxidative stress, or ROS [38]. To our knowledge, the [51]. Recent studies have claimed that upregulation of Nrf2
brain weighs just 2% of the body’s weight, but its metabolic provides neuroprotection against oxidative stress-induced
oxygen consumption accounts for 20% of total oxygen con- neurotoxicity in PD. Rb1 can enhance the transcriptional
sumption of the organism under nonstress conditions. High activation of Nrf2 and upregulate the expression of HO-1,
oxygen demand is always accompanied by more ROS. The an endogenous antioxidant enzyme and downstream effector
brain is rich in various polyunsaturated fatty acids sensitive of Nrf2, by modulating PI3K-mediated Nrf2-ARE signal
to ROS, but is relatively devoid of antioxidant enzymes and pathway, which is shown to serve as a rational cytoprotective
GSH, adding that neurons are considered terminally differ- agent against oxidative insults of dopaminergic cells [52].
entiated cells [39], which make brain tissue more inclined Taken together, ROS elevation initiates neuronal damage
to suffer damage from ROS [40, 41]. and we propose that Nrf2-related agents look set to offer an
Robust evidence suggests that ROS display a recognized up-and-coming clinical therapy.
role in neuronal death after brain ischemia [42]. Either an
initial burst of ROS induced by ATP consumption and 3. Autophagy
mitochondria depolarization in the ischemic phase or the
Ca+-dependent ROS generation at the reperfusion stage Autophagy was observed in mouse hepatocytes by Ashford
can pose a hazard for neurons [42]. As noted earlier, exces- and Porter for the first time in 1962 and visually described
sive production of ROS can not only damage cellular macro- as cellular self-eating [53]. Nevertheless, it was De Duve that
molecules but also impair antioxidant enzymes and first came up with the concept of autophagy in 1967 [54].
nonenzymatic antioxidants during I/R insult, which is unfa- Autophagy refers to macroautophagy in this review, the
vorable for neurofunctional recovery. Sharma and Airao most common and well-studied form, which is distinguished
have shown that lipid oxidation byproducts such as MDA from microautophagy and chaperone-mediated autophagy
are markedly increased in ischemic tissues, but SOD, CAT, (CMA) by the different degradation pathways of substrates
and GSH levels are reduced. Early administration of solaso- [55, 56]. Autophagy induction is a complicated and ordered
dine can ameliorate progressive ischemic injury through its multistep process, which mainly includes the following
potent antioxidant properties [43]. The Nrf2/ARE pathway steps: the signal stimulus, then autophagosome formation
is referred to as a potent defense mechanism against oxida- and fusion with lysosomes, and finally the degradation and
tive stress, which is expected to be a feasible direction of anti- release of its contents.
oxidant treatment against ischemia-reperfusion (I/R) injury. It has also been copiously reported that autophagy can
In the Shah and Li study, they found that Nrf2 knockout mice facilitate the renewal of cellular constituents to guarantee
in the I/R group present more obvious neurologic deficits energy and materials of quality needed to sustain metabolic
than the wild type group with a significant increase in the reactions, which orchestrates such biological processes as
area of infarction [44]. Enhancing the activation of Nrf2 by proliferation and differentiation of cells under various phys-
tBHQ, a natural Nrf2 inducer, can reduce and limit brain iological or pathological conditions [57]. Typically, autoph-
damage and is therefore possibly a practical prevention strat- agy exists at a low level and a basal rate in most cells [58],
egy for stroke-prone patients [45]. but it can be activated rapidly in response to excessive release
Studies have shown that the cellular damage in the early of ROS, abnormal aggregates of misfolded proteins, or a col-
stages of AD is ascribed to oxidative stress [46], and notably, lapse of mitochondrial membrane potential (MMP) apart
a large number of markers of oxidative stress are located in from infection, cancer, ATP, or nutrient deficiency [59, 60].
intracellular NFTs, a hallmark of the brains of AD patients It is well established that only adequate autophagy is a
[47]. A significant decrease in GPx and CAT activities and kind of cellular self-defense mechanism in times of oxidative
total GSH levels, which indicates a feeble antioxidant defense stress and other unfavorable conditions [61]. However,
system in early AD, may facilitate the development of the dis- improper autophagy above or below a certain threshold is
ease. Meanwhile, extensive experiments collectively verify instead disadvantageous [11], likely accelerating the progres-
that antioxidants do delay the occurrence and progression sion of all the related diseases such as neurodegenerative dis-
of AD [48]. These oxidative stress indicators are used to char- eases, cerebral ischemia, and cancer [62, 63].
acterize the earliest events of AD and are reliable tools for
early diagnosis and prevention of AD [49]. 3.1. Autophagy-Relative Marker Proteins. As discussed previ-
Recent progress in PD has revealed that dopaminergic ously, autophagic elimination is a highly sophisticated pro-
neurons are susceptible to oxidative stress because of inher- cess during which unwanted or redundant organelles and
ent biological features. Clear evidences show that 4-HNE bits of cytoplasm are enveloped then sweeped away in a
within such body fluids as CSF and serum is widely described lysosome-dependent manner. Each step is finely regulated
Oxidative Medicine and Cellular Longevity 5

by relevant proteins that were first discovered in yeast but discussing the PI3K-III complex, it is common to mention
later verified in higher organisms [63, 64]. that the class I PI3K and its downstream target AKT, as with
LC3 is a mammalian, homologous protein of Atg8 in MAPK/ERK1/2 signaling, which can exert negative regula-
yeast that has been identified to be the most widely used spe- tory effects at any stage of induction of autophagy via activat-
cific marker of autophagy initiation. LC3 is first synthesized ing mTOR [78].
as its precursor, then cut up into its cytosolic form, LC3-I, Arguably, distinct signaling pathways involved in the
which can be processed into LC3-II [65]. LC3-II specifically autophagic process vary with different adverse stimuli.
binds to the newly formed autophagosome essential for the AMP-dependent protein kinase (AMPK), an upregulated
elongation stage of the phagophore membrane. The amount modulator of autophagy, can sense subtle levels of ATP. On
of autophagosome can be mirrored by the expression of LC3- the one hand, AMPK can activate autophagy with a direct
II or LC3-II/LC3-I [66]. Mizushima et al. [67] were able to inhibitory effect on mTORC1 [79]. On the other hand, p-
dynamically trace the formation of autophagosomes by using AMPK can activate TSC1-TSC2 complex, indirectly sup-
fluorescence characteristics of GFP in established GFPLC3 pressing the activity of mTORC1 and concurrently initiating
transgenic mice, which greatly facilitated the study of the autophagy [80]. In addition, AMPK can also combine with
molecular mechanisms of autophagy. Beclin1, the first mam- ULK1 complex and phosphorylate ULK1, accelerating the
malian autophagy-related gene to be identified, regulates the progress of autophagic membrane formation [81] (Figure 2).
activity of autophagy particularly in the initiation phase by
combining with different ligands [68]. Beclin1 can modulate 3.3. Mitophagy. Past studies have argued that autophagy does
autophagic flux by interacting with PINK1 [69]. not select which substrates are to be degraded [82]. However,
In addition, there are observable changes of p62/SQSTM1 a widely accepted view, proposed in 2005, is that there is a
in the progression of canonical autophagy [70]. P62 is nega- selective form of autophagy in which damaged or unneces-
tively correlated with autophagy activity, reflecting the degra- sary mitochondria are eliminated [83]. This nonclassical
dative capability of autophagy and the intensity of autophagic autophagy was defined as mitophagy, and simultaneously
flux [71]. The receptor protein p62 can be recruited to the or successively, other types of selective autophagy such as
autophagosome membrane when LC3-interacting region xenophagy, pexophagy, ribophagy, and reticulophagy were
(LIR) motif targets a substrate (ubiquitinated protein aggre- also identified [59, 84].
gates, damaged mitochondria [72]) and initiates selective Mitochondria are a sensitive organelle ubiquitously
degradation in an autophagy-lysosome manner. found in eukaryotic cells. They are responsible not only for
energy-generating processes, but also for producing a basic
3.2. Autophagy-Relative Signal Pathway. Prevailing studies amount of ROS [85]. Mitochondria form a complicated net-
indicate that signal transduction pathways associated with work regulated by other cellular mechanisms, in which
autophagy may be more complex than the following two: the mitochondria are interconnected and interlocked in a per-
mammalian target of rapamycin (mTOR) pathway and the fectly coordinated order. Impaired mitochondria are a
class III phosphatidylinositol 3-kinase (PI3K-III) complex. threat to proper cellular function because they result in a
Mammalian target of rapamycin (mTOR), a serine/ lack of energy generation and excessive release of ROS
threonine protein kinase, is engaged in autophagy modula- [86]. Therefore, it is urgent that dysfunctional mitochondria
tion as a dominant downstream negative regulator [73]. that interfere with the energy supply and provoke oxidative
mTOR complexes exist in two types, namely mTORC1 and stress be quickly removed [87]. Fortunately, mitophagy
mTORC2, which are distinguished by different components. can shoulder this responsibility as an effective cytoplasmic
mTORC1, a regulatory associated protein composed of Ric- protection mechanism.
tor, has been demonstrated to terminate the autophagy pro- Mitophagy is a programmed mitochondrial elimination
gression as a critical signaling molecule that is susceptible mechanism that fosters a balance of mitochondrial quantity
to the strong inhibition of rapamycin [74, 75]. When cells and quality [59, 87]. It usually occurs in the case of an
suffer hypoxia, energy depletion, and other stimuli, mTORC1 abnormal increase of ROS, poor nutrition, hypoxia [88],
activity is simultaneously restrained with the activation of cells senescence, and such stress. These stimuli can cause
autophagy. Suppressed mTORC1 plays a causal role in the mitochondrial membrane depolarization or a loss of MMP.
activation of ULK1 complex by dephosphorylating the Pathological opening of the mPTP may serve as the switch
autophagy-related gene13 (Atg13) and mediating a tighter for mitophagy. Existing studies suggest that there are two
combination of ULK1, Atg13, and FIP200. ULK1 is homolo- relatively recognized mitophagy pathways involved in mito-
gous with Atg1 in yeast, which has been found to be involved chondrial homeostasis. These two pathways are the PINK1/
in the induction of autophagy. The ULK1-Atg13-FIP200 Parkin-mediated pathway and the Bnip3/Nix-mediated
complex is not only a direct target of mTOR but a key regu- pathway. The PINK1/Parkin-mediated pathway is closely
lator of other autophagy-related signaling pathways. associated with Parkinson’s disease and is a topic of current
The PI3K-III complex is composed of VPS34 (catalytic research [89].
subunit), Beclin1, and Atg14. When activated by the ULK1
complex, the PI3K-III complex is positioned into the endo- 3.3.1. PINK1/Parkin-Mediated Pathway. PINK1, a serine/
plasmic reticulum and further generates PI3P that binds to threonine protein kinase, is located on the outer membrane
downstream effectors, playing an important role in the earlier of mitochondria and is the upstream regulator of Parkin
period of autophagic vacuole formation [76, 77]. When [90]. Parkin is an E3 ubiquitin ligase, which is present in
6 Oxidative Medicine and Cellular Longevity

Nutrient deficiency Hypoxia

ATP deficit Neurodegeneration
ROS accumulation Infection
Protein aggregation Cancer

PI3K mPTP
휓m

Mitochondrial
dysfunction
TSC1 ATP
Akt TSC2 AMPK
AMP Parkin
LC3
Parkin
Bnip3/Nix
Raptor PINK1

mTORC1 LC3
VPS34 Atg14 p62/SQSTM1
Ub VDAC1 Drp1
Beclin1 Mfn1/2
ULK1 Autophagy Fis1

PI3K-III complex FIP200 Atg13

Mitophagy

Figure 2: The generation and scavenging of reactive oxygen species (ROS) in mitochondria. The “→” refers to activation or induction, and
the “⊢” refers to inhibition. Under normal or stress conditions, ROS is mainly born from the mitochondrial respiratory chain with the
beginning of O2− production, followed by the conversion to H2O2 then OH− under the catalysis of SOD and GSH-px. Defective
mitochondria can instigate ROS accumulation with a “RIRR” positive-feedback mechanism. Excessive ROS can inflict severe damage on
biomacromolecules, which can be counteracted by the antioxidant enzyme system to some degree.

the cell plasma [91] but has no mitochondrial targeting shown that Bnip3/Nix directly interacts with LC3 to activate
sequence (MTS) [92]. As a matter of fact, PINK1 can be the mitophagy pathway [97, 98]. Some researchers believe
degraded away quickly by proteolytic enzymes in healthy that though Bnip3 and Nix are involved in mitophagy upon
mitochondria. In the disturbed mitochondria, it will accumu- the loss of mitochondrial membrane potential, they may exe-
late following depolarization of the membrane potential, cute mitochondrial clearance via independent but function-
phosphorylate Parkin, and then recruit Parkin from the cyto- ally related mechanisms [99, 100] (Figure 2).
plasm [90]. Along with strengthening E3 ubiquitin ligase Additionally, Mieap can also induce mitophagy after ROS
activity, Parkin can ubiquitinate the mitochondrial matrix and oxidative damage to restore a healthy pool of mitochon-
proteins (voltage-dependent anion-selective channel protein dria [101]. Last but not least, mitochondrial fusion, division,
1, VDAC1), recruit p62/SQSTM1 to the surface of mitochon- and transportation are tightly linked to mitophagy [102].
dria, and then combine with LC3 to initiate mitophagy [93].
Emerging research indicates that RAD6A (Ube2a), a gene 3.4. Autophagy in Neurological Disorders. Not surprisingly,
encoding ubiquitin binding enzyme (E2) that is required for autophagy is extensively observed in nervous system disor-
the ubiquitination and subsequent clearance of defective ders [61]. It has long been thought that autophagy is the
mitochondria, can operate with Parkin to regulate mitophagy primary means for the biodegradation of abnormal protein
upon mitochondrial depolarization in mice cortical neurons. aggregation and dysfunctional organelles in CI, AD, and
Whether the program is dependent on PINK1 needs further PD [103]. Defects in mitochondrial autophagy will aggravate
scrutiny [94]. ischemic tissue damage with irreversible neurologic deficit
[104], render cognitive and memory defects in AD as a con-
3.3.2. Bnip3/Nix-Mediated Mitophagy. Bnip3, a proapoptotic sequence of progressive aggregation of Aβ [105], and pro-
protein, has some degree of homogeneity with BCL-2. Nix is mote dopaminergic neuronal death and the occurrence of
56% homologous with Bnip3. Both widely existed in mito- PD [106]. These results of defects in mitochondrial autoph-
chondria and are implicated with autophagy and mitophagy agy indicate that mitophagy acts as an endogenous protective
in particular [95]. Bnip3 induces autophagy after hypoxic mechanism in the process of neurological disorders. At pres-
damage and has been reported to have a protective effect by ent, although a growing number of studies have argued that
removing injured mitochondria [96]. Recent studies have autophagy is activated in various rat and mouse models of
Oxidative Medicine and Cellular Longevity 7

cerebral ischemia or hypoxia-ischemia [9, 107–110], whether serves as a cytoprotective process to limit the production of
autophagy is protective or detrimental in the process of CI ROS and avoid potential oxidant injury [122].
still remains unclear [111]. It is also believed that a number of signal transduction
pathways related to autophagy are available to modulate
4. Reactive Oxygen Species ROS. The Keap1-Nrf2 system is now considered a defense
(ROS) and Autophagy mechanism upon exposure to oxidative stress [123, 124]. As
mentioned earlier, the p62/SQSTM1 protein, or p62 for
A growing body of reports has demonstrated that most short, may contribute to autophagosome formation as an
stressful events, such as nutrient deficit and hypoxia, which autophagic adaptor and/or receptor [125]. Phosphorylation
necessitate a greater energy supply and then aggravate mito- of P62 in the mTORC1-dependent autophagy pathway can
chondrial burden along with increasing ROS, are related to promote the integration of ubiquitinated cargos and phos-
the initiation of autophagy [16]. Intriguingly, an increasing phorylated Keap1, which is necessary for the degradation of
amount of evidence suggests that ROS are seen as essential Nrf2 [126, 127]. Released Nrf2 is reactivated, translocated
signals to activate autophagy under various stimulating con- into the nucleus while binding to ARE, and eventually stim-
ditions [112, 113]. Both moderate and increased ROS levels ulates transcription of antioxidant genes. Beyond that, mito-
can specifically trigger mitophagy which is conducive to cell chondrial hexokinase II (HKII) shares a deep relationship
survival in a different manner, while only excessive ROS with autophagy and redox homeostasis. HKII induces the
can activate general autophagy [114]. inactivation of mTORC1, further opens mPTP, and creates
The molecular signaling pathways involved in both the a preventive antioxidant defense by decreasing release of
initiation and execution of autophagy following exposure to ROS [128, 129].
ROS are sophisticated [16, 18]. The pathways mainly include In conclusion, there is little doubt that ROS play a posi-
transcriptional progress in the nucleus and posttranscrip- tive role in the activation of autophagy under various stimu-
tional progress in the cytoplasm. These specific transcrip- lating conditions [112, 113]. By coincidence, autophagy plays
tional regulatory mechanisms first involve the activation of a crucial role in maintaining redox homeostasis [6]. ROS can
HIF-1, p53, FOXO3, and NRF2; then, the corresponding pro- induce autophagy, and autophagy serves as a buffer system to
teins are produced and modulation of autophagy occurs control the level of ROS in cells and reduce their toxic effects
where the cytoplasm was exposed to ROS. Take hypoxia- [130]. The interplay of autophagy and redox response via
inducible factor (HIF) for example, it is involved in cell sur- various signaling pathways may be involved with the modu-
vival under hypoxic conditions and participates in the tran- lation of cellular homeostasis [127] (Figure 3).
scription of Bnip3 and NIX in response to ROS. These
autophagy-associated protein products can constitutively 4.1. Reactive Oxygen Species (ROS) and Mitophagy. As stated
stimulate autophagic clearance of damaged mitochondria earlier, mitochondria are believed to be the primary source of
and decrease ROS levels [115]. ROS. Coincidentally but unfortunately, they are also the
In addition, numerous studies have supported that ROS major target of oxidative stress triggered by ROS, which
may regulate autophagy via mTOR-dependent pathways in may result from the fact that mitochondria are an important
the cytoplasm [116–118]. Nevertheless, most of the literature site for nucleic acid, lipid, and amino acid production. Exces-
maintains that ROS available to elicit autophagy are mainly sive ROS stimuli can inflict peroxidation damage on these
H2O2 and O2− produced by mitochondria [14, 112]. When biomacromolecule precursors and create toxic byproducts
there is an elevated level of H2O2, a relatively stable and pro- [131]. Note that mtDNA lacks the protection of histones,
longed stimuli, suppressed autophagy via the PI3K-Akt and its repair capacity is rather poor. It is therefore more vul-
pathway, can be reactivated by blocking PTEN as well as nerable to ROS than nuclear DNA [132] and is bound to
inhibiting the activity of Akt or mTORC1 [119]. Similarly, leave mitochondria heavily damaged by ROS.
H2O2 in excess can induce autophagy in an AMPK- Mitochondrial dysfunction caused by a high concentra-
dependent manner and is accompanied by the decline of tion of ROS not only can activate and regulate nonselective
mTORC1 activity [18]. Beyond that, a wide range of stress autophagy, but also can be involved in mitophagy which
response proteins such as p38MAPK, extracellular regulated selectively removes damaged mitochondria. ROS and oxida-
kinase (ERK), and c-Jun N-terminal kinase (JNK) is also tive stress have been shown to be involved in the recruitment
involved with autophagy induction in the presence of and localization of Parkin and DJ-1, specific proteins that are
abundant ROS [120]. Taken together, it is an indisputable closely tied to the activation of mitophagy [133].
fact that ROS is an available regulator despite autophagy Selective autophagy is a protective mechanism that reduces
making a difference in both cell survival and death as a ROS production by means of removing unneeded mitochon-
double-edged sword. dria, thereby alleviating oxidative damage [16, 122]. More
From another perspective, autophagy has been proposed importantly, defects in mitophagy can aggravate lipotoxicity,
as a potential survival mechanism in the face of ROS produc- hinder selective degradation of defective mitochondria
tion by removing damaged or redundant components to pre- caused by ROS, and thus cause subsequent damage to the
vent unnecessary oxidative damage [19]. Furthermore, there cells [134].
are increased intracellular ROS levels in cells with defective Haddad et al. [94] discovered that RAD6A can cooperate
autophagy protein Atg7 [121]. Specially, the selective elimi- with Parkin to ubiquitinate mitochondrial proteins associated
nation of dysfunctional mitochondria via autophagy also with the initiation of mitophagy for clearing dysfunctional
8 Oxidative Medicine and Cellular Longevity

Figure 3: The interrelation of ROS and autophagy/mitophagy, coupled with the relevant signal transduction pathways. ROS available to
induce autophagy is mainly mitochondrial H2O2 and O2−, which may modulate autophagy via mTOR-dependent pathways. ROS-induced
autophagy and mitophagy both can abort ROS for redox homeostasis. In response to abundant ROS, the Keap1/Nrf2/ARE cascade is
activated as a potent antioxidant mechanism. Phosphorylation of P62 by autophagy can promote the integration of phosphorylated Keap1
and ubiquitinated Nrf2, then negative regulation of Keap1 frees Nrf2 from degradation, and reactivated Nrf2 is translocated into the
nucleus to bind to ARE for the transcription of antioxidant genes and phase II enzymes.

mitochondria and dampening oxidative stress. Particularly, reperfusion following ischemia results in a more serious
RAD6A mutations cause neuronal function defects primarily brain damage [141]. The ischemia-reperfusion injury is a
by disrupting mitophagy (Figure 3). complicated pathological process involving multiple factors,
among which oxidative stress stands out [5, 142]. There is
4.2. Reactive Oxygen Species (ROS) and Autophagy an extensive damage of mitochondria, including irregular
(Mitophagy) in Neurological Disorders. ROS are described as mitochondria swelling and their crista fragmenting, in CI
the culprit of almost all neurological conditions [135]. Mount- especially during the acute phase. This damage stimulates
ing evidence has indicated that ROS participate actively in mPTP to open continuously, leading to a change in mem-
autophagy in many cells, including neurons [131, 136]. brane potential, energy deficit, and ROS generation, thus
Autophagy removes or degrades nonfunctional cytoplasmic inducing autophagy.
content as an intracellular self-purification mechanism. Neu- It has been observed that autophagy occurs dramatically
rons are highly sensitive to autophagic degradation, and the in the mouse striatum and cortex following cerebral
integrity of mature neurons depends on the high level of hypoxic-ischemic injury and can then be strongly amplified
autophagy because of their postmitotic nature [14, 137]. by an ensuing overproduction of ROS. Autophagy in this
Also, autophagy can reduce ROS damage by eliminating context can substantially rescue neurons in the ischemic pen-
unnecessary or damaged organelles and abnormal protein umbra by preventing necrosis and apoptosis via eliminating
aggregates, as well as inhibiting the excessive activation of impaired mitochondria [143].
ROS in response to neuronal damage, which is conducive It has been reported that FA deficiency dramatically
to the survival of nerve cells [138]. Emerging evidence indi- alters ischemia-induced activation of autophagy. This is
cates that autophagy may exhibit an antioxidant defense sys- reflected by the elevated levels of LC3 and Beclin1 expression,
tem, which has been proposed to provide a remarkable which are accompanied by a remarkable increase in 8-
impact on neuronal bioenergetic health [139]. OHdG, indicating that FA deficiency may enhance autoph-
agy levels by triggering oxidative damage [144]. One study
4.2.1. Reactive Oxygen Species (ROS) and Autophagy has shown that both ROS and autophagy are engaged in
(Mitophagy) in CI. Ischemic cerebrovascular disease (CI) is reperfusion injury after cerebral ischemia and that autophagy
a leading cause of death and disability worldwide [140]. Cur- can be activated by antioxidants. The application of antioxi-
rently, endovascular intervention and venous thrombolysis dants or autophagy revulsive can reduce neuronal damage
are conventional therapies for restoring the blood supply and significantly decrease the infarction area [145]. Thus,
required for the recovery of nervous function. However, both we can speculate that antioxidants might play a protective
animal studies and clinical findings have revealed that role in ischemic injury by inducing autophagy. There may
Oxidative Medicine and Cellular Longevity 9

Table 1: The interplay between ROS and autophagy/mitophagy in neurological diseases.

Effect of
Author Year Model (animal/cell) Main idea
autophagy
FA deficiency simultaneously enhanced the activity of autophagy and
induced the generation of oxidative stress following the MCAO
Zhao et al. [144] 2016 MCAO/SD rats Detrimental
model; oxidative injury seems to be involved in excessive activation of
autophagy caused by FA deficiency.
Autophagy is upregulated, and the level of ROS is elevated in the
central nervous system after ischemia-reperfusion; Antioxidants can
Wenjing et al. [145] 2013 Mouse & neural cells Protective
protect neural cells and decrease infarct volume possibly by activating
the autophagic pathway of cells.
Chemical inhibitors of autophagy or lysosomes can delay the release
of mitochondrial ROS to prolong the therapeutic time window.
Kubota et al. [146] 2010 MCAO/SD rats Ischemic insults will immediately initiate autophagy induction with Detrimental
undefined mechanisms, which significantly will impact ROS
production and oxidative damage in vivo.
Sirt3 showed a protective role in eliminating intracellular H2O2,
Dai et al. [147] 2017 OGD/cortical neurons attenuating mitochondrial O2−, and promoting autophagy through Protective
the AMPK-mTOR pathway in neuronal ischemia.
SIRT6-mediated autophagy contributes to oxidative stress-induced
SH-SY5Y/neuronal neuronal injury since inhibition of autophagy could prevent the
Shao et al. [149] 2016 Detrimental
cells detrimental effect of SIRT6 on cell survival, which could be attributed
to attenuation of AKT signaling closely related to oxidative stress.
The autophagic removal of Aβ mediated by Parkin can attenuate
Khandelwal et al. [105] 2011 3xTg-AD mice oxidative stress and mitochondrial dysfunction to restore energy Protective
supply for a better modulation of autophagy in AD transgenic mice.
Autophagy is proposed as an antioxidant protective pathway that can
clear cumulative ROS and reverse established ROS-induced protein,
Giordano et al. [154] 2014 PD mouse model Protective
DNA, and lipid damage independent of the disposal of radical
scavengers.
Autophagy can scavenge aggregate-prone proteins and increased
Mouse cortical ROS, while antioxidants can block autophagy and thereby
Underwood et al. [155] 2010 Protective
neurons counterbalance the benefits of autophagy and exacerbate
neurodegeneration.
Loss of PINK1 function can stir oxidative stress, which can then elicit
PD cell
Dagda et al. [159] 2009 coordinated autophagy and mitophagy for mitochondrial turnover by Protective
model/SH-SY5Y
a removal of dysfunctional mitochondria.

be some more complicated mechanisms of crosstalk between in vivo mechanistic studies are needed to verify the interplay
autophagy and oxidative stress in need of further research. of oxidative stress and autophagy. Furthermore, moderate
One study pointed to the finding that ischemic insults could activation of ROS can promote the translocation of Parkin
immediately activate autophagy as a neuroprotective mecha- to injured mitochondria and then incur Parkin-mediated
nism, which significantly affects ROS generation and oxidative mitophagy and ensure the integrity of mitochondria in ische-
toxicity. As well, pharmacological inhibition of autophagy or mic brain injury [150] (Table 1).
lysosomes can delay the mitochondrial ROS burst [146].
Scherz-Shouval and Elazar [15] have argued that ROS can 4.2.2. Reactive Oxygen Species (ROS) and Autophagy
upregulate autophagy through multiple signaling pathways. (Mitophagy) in AD. Alzheimer’s disease (AD) is one of the
Sirt3 is a conserved deacetylase associated with biological most common types of late-onset neurodegenerative diseases,
functions such as energy metabolism, stress resistance, and hallmarked by a progressive loss of memory and cognition
mitochondrial redox homeostasis. Furthermore, it can posi- coupled with typical pathological features including neuritic
tively regulate autophagy through the AMPK-mTOR path- plaques (NPs) and neurofibrillary tangles (NFTs) [46, 151].
way [147], which promotes neuronal survival within an Enhanced ROS and oxidative damage have been proven to
in vitro oxygen and glucose (OGD) deprivation model of be implicated in the evolution of neuronal dysfunction during
cerebral ischemia created by attenuating H2O2 and O2− the early events of AD [152].
[148]. Pharmacological or genetic inhibition of autophagy Growing evidence suggests that spatial learning and
can ameliorate SIRT6-mediated neuronal injury, probably memory deficits in AD may be tightly correlated with the
via attenuating AKT signaling closely related to oxidative impairment of the Nrf2-ARE pathway since Nrf2 knockout
stress in the OGD model of SH-SY5Y neurons [149]. Further, confers AD model mice with more sensitivity to neuronal
10 Oxidative Medicine and Cellular Longevity

damage. Strikingly, some scholars have proposed that the mediated mitophagy [160]. Both DJ-1 and DJ-1-binding
interaction between oxidative stress and mitochondrial dys- compounds have been identified as neuroprotective against
function may be involved in the process of AD because of oxidative stress in PD rats [161].
the influence oxidative stress has on mitochondrial trans-
port [153]. It has been observed that autophagic vacuoles 5. Conclusion and Perspective
with engulfed, defective mitochondria increased in the
pyramidal neurons of AD patients [7]. The autophagic Plenty of studies have repeatedly shown that ROS accumula-
removal of damaged mitochondria and Aβ mediated by tion displays detrimental implications for the basic function
Parkin can attenuate oxidative stress and restore the energy and survival of neurons. ROS or oxidative stress can provoke
supply so as to delay or prevent neurodegeneration in AD autophagy, and autophagy can take part in the removal and
transgenic mice [105] (Table 1). repair of ROS-induced oxidative lesions through a variety
of signaling pathways. But autophagic neuronal death will
4.2.3. Reactive Oxygen Species (ROS) and Autophagy still result if cumulative ROS go beyond the scavenging activ-
(Mitophagy) in PD. Parkinson’s disease (PD) is a movement ity of autophagy. At present, it appears to be contradictory
disorder with three outstanding clinical characteristics: bra- that autophagy serves as a cellular self-purification mecha-
dykinesia, resting tremor, rigidity, and postural instability. nism, but hyperactivity or hypoactivity of autophagy is unfa-
Although the underlying etiology of PD is still far from clear, vorable for the normal functionality of neurons [162, 163].
oxidative stress and mitophagy deficiency have been proposed After all, the predetermined threshold level of perfect
as the principal elements in the development of dopaminergic autophagy is often blurred, particularly under a variety of
neuronal death in the substantia nigra of PD patients. disease courses. So, more relevant, constructive research
Neurodegenerative diseases such as PD are often accom- should be undertaken without delay.
panied by increased oxidative brain damage coinciding with Mitochondria are thought to be crucial for neuronal
a reduction in antioxidants. This leads to dysfunctional function and fate by supplying energy and modulating
mitochondria or protein aggregates that can be rescued to redox status. It is well established that brain mitochondrial
some extent by radical scavengers. Autophagy has been pro- dysfunction or mitophagy defects are strongly associated
posed as an endogenous, antioxidant, protective pathway with the initiation and progression of CI, AD, and PD.
that can clear accumulated ROS and reverse established Neuronal mitochondrial impairments exhibit pronounced
ROS-induced protein, DNA, and lipid damage independent effects on mitochondrial membrane potential, leading to
of the disposal of radical scavengers [154]. Protein accumu- the prolonged opening of mPTP and an elevated produc-
lation and oxidative stress are pathologically pronounced in tion of ROS which can be rescued by mitophagy and
neurodegenerative diseases. Enhancing autophagy could ensuing mitochondrial turnover. Concurrently, treatment
scavenge aggregate-prone proteins and increased ROS, while with mitochondria-targeted antioxidants substantially mit-
antioxidants could block the benefits of autophagy and exac- igates neuronal mitochondrial disturbance and oxidative
erbate neurodegeneration [155]. damage [164, 165].
Mitochondria have a central role in redox regulation of In summary, we provided a basic knowledge of ROS and
autophagy as the generator and scavenger of ROS [156], autophagy/mitophagy and then expatiated specifically on the
but can be attacked when ROS exceed the scavenging activity. interrelation between ROS and autophagy as well as on their
The dysfunction of mitochondria is a prominent initiating molecular regulatory mechanisms. Finally, we discussed the
factor of nervous system diseases [157]. This dysfunction interplay of ROS and autophagy in CI, AD, and PD. None-
then amplifies oxidative damage, with the underlying theless, a lot of current work only focuses on the close inter-
assumption that the quality and quantity of mitochondria play between ROS and autophagy/mitophagy in CI and PD,
significantly affects neuronal function. Mitophagy was origi- while there are few studies on how they are involved in AD
nally proposed to clear disturbed mitochondria after patho- and the underlying, precise, regulatory mechanisms are not
logical stress in an attempt to restore homeostasis [158]. well investigated. In the future, more basic research is needed
Dagda et al. discovered that knockdown of PINK1 in a to further excavate the correlation between autophagy/mito-
recessive PD model can result in the accumulation of mito- phagy and ROS together with their possible mechanisms in
chondrial ROS, accompanied by clustered fragmented mito- neurological disorders. Such research will lay a good founda-
chondria and depolarized mitochondria which correlate tion for pinpointing late-model drug targets and exploring
with autophagy. More importantly, autophagy does play aggressive therapeutic tactics that are applicable for the clin-
an essential role in limiting dopaminergic neuronal death ical treatment of such life-threatening neurological diseases.
in this genetic model and RNAi knockdown of genes neces-
sary for inducing autophagy exacerbates the occurrence of Conflicts of Interest
PD [159] (Table 1).
Several studies have claimed that mitochondrial dysfunc- The authors have no conflicts of interest.
tion and the existence of mitochondrial complex Ι defects
also contribute immeasurably to the disease by playing a Authors’ Contributions
causative or consequential role in the exacerbation of oxida-
tive stress in dopaminergic neurons. DJ-1, a causative protein Congcong Fang and Lijuan Gu equally contributed to
of familial PD, is essential for modulating PINK/Parkin- this work.
Oxidative Medicine and Cellular Longevity 11

Acknowledgments [17] Y. Mi, C. Xiao, Q. Du, W. Wu, G. Qi, and X. Liu, “Momordin
Ic couples apoptosis with autophagy in human hepatoblas-
This work was supported by the National Natural Science toma cancer cells by reactive oxygen species (ROS)-mediated
Foundation of China (no. 81771283 to Lijuan Gu and no. PI3K/Akt and MAPK signaling pathways,” Free Radical Biol-
81571147 to Xiaoxing Xiong). ogy & Medicine, vol. 90, pp. 230–242, 2016.
[18] R. Scherz-Shouval, E. Shvets, and Z. Elazar, “Oxidation as a
post-translational modification that regulates autophagy,”
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