Table 1. Redox modification of autophagy proteins and impact of autophagy deficits on oxidative stress.

Summary of the current literature on the impact of alterations of autophagy gene levels on mitochondrial function and cellular oxidative stress. Many of these observations have been mentioned in the text. Furthermore, specific examples of protein modifications of autophagy regulatory molecules in response to ROS/RNS alterations are also listed.

Autophagy gene	Impact on mitochondrial function	Impact on oxidative stress	Redox modification
ULK1	ULK1 knockout results in decreased mitochondrial clearance during reticulocyte maturation [27]
FIP200	The livers from FIP200 knockouts exhibit significant increase in mitochondrial mass [139]	The livers from FIP200 knockouts exhibit significant increase in ROS [139]
mTOR	Rapamycin treatment, or siRNA knockdown of TSC2 (tuberous sclerosis complex 2), S6K1 (ribosomal S6 kinase 1), raptor (regulatory associated protein of mTOR) or rictor (rapamycin-insensitive companion of mTOR), lowered the mitochondrial membrane potential and oxygen consumption [278]		NO-induced S-nitrosation of IKKβ inhibits its activity and prevents the inactivation of TOR [110]
Atg3	Atg3−/− T-cells exhibited reduced autophagy and expanded mitochondria [279]	Atg3−/− T-cells exhibit increased ROS production [279]
Atg4	Atg4b knockout results in decreased proteolytic processing of LC3A, LC3B, GABARAP and Atg8L [280]. Atg4d has an affinity for damaged mitochondria in cells treated with H2O2 [281]		Starvation and H2O2 induce Atg4 thiol modification, which is important for autophagy [80]
Atg5	Atg5−/− cells have deformed and dysfunctional mitochondria [282,283]. Mitochondrial gene regulation is significantly altered in Atg5−/− T-cells [284]. Mitochondrial content and cross-sectional mitochondrial surface area are increased in Atg5−/− T-cells [285]	Atg5−/− cells exhibit accumulation of ubiquitinated proteins and accumulation of ROS [80,142,143,283]. Reduction of Atg5 and Atg10 further increases ROS in response to starvation [81]. Genes involved in ROS generation are significantly altered in Atg5−/− T-cells [284]
Atg7	Reticulocyte maturation is diminished, but not abolished in Atg7−/− mice [286]. Atg7−/− erythrocytes accumulate damaged mitochondria [287]. Mitochondrial content and cross-sectional mitochondrial surface area are increased in Atg7−/− T-cells [285]. Haemopoietic stem cells that are Atg7-deficient accumulate mitochondria with high membrane potential [288]. Atg7−/− MEFs (mouse embryonic fibroblasts) exhibit dysfunctional mitochondrial respiration [142]	Atg7−/− cells have increased ROS [285]. Haemopoietic stem cells with Atg7 deficiency exhibit enhanced mitochondrial superoxide accumulation [288]. p62 and ROS are increased in Atg7−/− cells [142]
Beclin/Atg6	Apoptosis-deficient Bcl-2-overexpressing iBMK (immortalized baby mouse kidney) cells undergo autophagy in response to stress. Abnormal mitochondria accumulate in either Beclin+/− (Beclin haploinsufficiency) or Atg5−/− animals [270]	ROS accumulate in either Beclin+/− or Atg5−/− animals [270]	NO-induced S-nitrosation of JNK1 inhibits its activity and prevents the release of beclin from binding to Bcl-2 [110]
Atg8 (LC3B)	In response to LPS (lipopolysaccharide), LC3B−/− macrophages had more swollen mitochondria with severely disrupted cristae [289]	LC3B−/− macrophages generate more superoxide [289]
Nix	Decreased clearance of mitochondria in erythrocyte maturation [290]
Parkin	Parkin-deficient fibroblasts in Nix−/− mice exhibit altered mitochondrial morphology and activities [240]		Parkin can be inhibited by S-nitrosation [238]
PINK1	PINK1−/− mice exhibit impaired mitochondrial respiratory activities [241]. PINK1-deficient dopaminergic neurons accumulate fragmented mitochondria [242]. Down-regulation of PINK1 in neuroblastoma SH-SY5Y cells induced mitochondrial fragmentation [243]	PINK1−/− mice exhibit increased sensitivity to oxidative stress [241]. PINK1-deficient dopaminergic neurons accumulate mitochondrial superoxide [242]
DJ-1	Knockout of DJ-1 in fruitflies reduced the RCR (respiratory control ratio) and mitochondrial DNA/nuclear DNA ratio without changing membrane potential or complex I subunit NDUFS3 [NADH dehydrogenase (ubiquinone) 1β subcomplex 8] level [244]. DJ-1−/− mice exhibit reduced skeletal muscle ATP [244], down-regulated UCP4 and UCP5 [245–247], and reduced mitochondrial length and fusion rate [248]. Stable knockdown of DJ-1 in neuroblastoma cells led to a reduction in mitochondrial membrane potential, mitochondrial fragmentation and accumulation of LC3 around mitochondria. Overexpression of DJ-1 protects against rotenone-induced mitochondrial fragmentation; this function is independent of PINK1 [248,250]	DJ-1−/− mice exhibit increased sensitivity to oxidative stress, and increased H2O2 [245–247]. Addition of glutathione or NAC attenuates DJ-1-deficiency-induced phenotypes [248–250].