Mitochondrial quality control (QC) mechanisms encompass the removal of damaged mitochondrial components by the mitochondrial lon protease, mitochondrial dynamics (fusion and fission) and whole organelle degradation (mitophagy), thus ensuring the maintenance of a healthy mitochondrial population.1,2
Failure of mitochondrial QC is proposed to participate in the development and progression of Alzheimer and Parkinson diseases as well as in the aging process. While mitochondrial QC is an ongoing process, it becomes specifically important in the management of reactive oxygen species (ROS)-induced damage, as ROS are produced by the mitochondrial respiratory complexes I and III and affect primarily mitochondrial DNA (mtDNA), lipids and proteins.
After oxidative damage, mitochondria can either be degraded via mitophagy or rescued by mitochondrial dynamics. mtDNA and mitochondrial proteins including the complexes of the respiratory chain can be exchanged by fusion and fission.3–6
An intact membrane potential is necessary for the fusion of the inner mitochondrial membrane, and thus the exchange of inner membrane proteins and matrix components.7
We actually observed a decline of mitochondrial dynamics after addition of hydrogen peroxide,8
implying that mitochondrial dynamics may not be the primary QC mechanism utilized after oxidative stress.
Therefore, it seems more likely that a damaged mitochondrion or a mitochondrial segment separated by fission will be degraded by mitophagy.9
The signal that initiates autophagy of a damaged mitochondrion is still unclear; however, a loss of mitochondrial membrane potential and mitochondrial fragmentation9,10
as well as translocation of the PARK2-associated ubiquitin ligase Parkin from the cytosol to the mitochondrion11,12
are involved in the initiation of the autophagic process. During mitophagy the dysfunctional mitochondrion is engulfed by a membranous structure, the phagophore, which expands into an autophagosome. After fusion with endosomes and/or lysosomes the contents of the autolysosome are degraded.
The proteins of the ATG family regulate autophagy. ATG5, ATG12 and LC3B (ATG8F) all participate in the formation of the autophagosome. ATG5 forms a complex with ATG12 and ATG16L at the membrane of the evolving autophagosome.13
The 18-kDa isoform LC3-I is localized in the cytosol and after conjugation to phosphatidylethanolamine the activated 16-kDa isoform LC3-II is situated within the autophagosomal membrane.14
The lysosomal protein LAMP-1 is a glycoprotein that colocalizes with lysosomal staining and in cooperation with LAMP-2 participates in the autophago-lysosomal pathway.15
Furthermore, LAMP-1 and LAMP-2 are thought to mediate fusion of phagosomes with late endosomes.16
According to the “garbage theory of aging,” an accumulation of ROS-damaged molecules mediated by dysfunctional QC contributes to aging.17
This theory is supported by a decrease of mitochondrial dynamics in senescent cells,18,19
reduced expression of different autophagosomal proteins in old D. melanogaster20
and decrease of the lysosomal protein LAMP-2A in the livers of old rats.21
Caloric restriction and insulin resistance extend the life span of different model systems,22–25
and enhanced autophagy might be one of the main reasons behind the increased life spans.26–28
This hypothesis correlates with data that demonstrate increased life span of D. melanogaster
after overexpression of ATG8A20
and extended life span of yeast after treatment with the autophagy-inducing drug rapamycin.29
In contrast, some autophagy genes such as the ATG1 homolog ULK3 are upregulated in senescent human diploid fibroblasts, and overexpression of ULK3 results in premature senescence of these cells, accordingly implying a role of ULK3 in the mediation of senescence.30
Taken together, the role of mitochondrial QC and of the different autophagy genes after ROS damage and in the aging process are still unclear. Therefore, we analyzed the QC mechanisms after oxidative stress and the role of the involved ATG proteins ATG5, ATG12 and LC3B in regard to mitochondrial fitness and life span.