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Accumulation of PINK1 on the outer mitochondrial membrane (OMM) is necessary for PINK‐mediated mitophagy. The proton ionophores, like carbonyl cyanide m‐chlorophenylhydrazone (CCCP) and carbonyl cyanide‐4‐(trifluoromethoxy)phenylhydrazone (FCCP), inhibit PINK1 import into mitochondrial matrix and induce PINK1 OMM accumulation. Here, we show that the CHCHD4/GFER disulfide relay system in the mitochondrial intermembrane space (IMS) is required for PINK1 stabilization when mitochondrial membrane potential is lost. Activation of CHCHD4/GFER system by mitochondrial oxidative stress or inhibition of CHCHD4/GFER system with antioxidants can promote or suppress PINK1 accumulation, respectively. Thus data suggest a pivotal role of CHCHD4/GFER system in PINK1 accumulation. The amyotrophic lateral sclerosis‐related superoxide dismutase 1 mutants dysregulated redox state and CHCHD4/GFER system in the IMS, leading to inhibitions of PINK1 accumulation and mitophagy. Thus, the redox system in the IMS is involved in PINK1 accumulation and damaged mitochondrial clearance, which may play roles in mitochondrial dysfunction‐related neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

GGGGCC repeat expansion in C9orf72 is the most common genetic cause in both frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), two neurodegenerative disorders in association with aging. Bidirectional repeat expansions in the noncoding region of C9orf72 have been shown to produce dipeptide repeat (DPR) proteins through repeat‐associated non‐ATG (RAN) translation and to reduce the expression level of the C9orf72 gene product, C9orf72 protein. Mechanisms underlying C9orf72‐linked neurodegeneration include expanded RNA repeat gain of function, DPR toxicity, and C9orf72 protein loss of function. In the current study, we focus on the cellular function of C9orf72 protein. We report that C9orf72 can regulate lysosomal biogenesis and autophagy at the transcriptional level. We show that loss of C9orf72 leads to striking accumulation of lysosomes, autophagosomes, and autolysosomes in cells, which is associated with suppressed mTORC1 activity and enhanced nuclear translocation of MiT/TFE family members MITF, TFE3, and TFEB, three master regulators of lysosomal biogenesis and autophagy. We demonstrate that the DENN domain of C9orf72 specifically binds to inactive Rag GTPases, but not active Rag GTPases, thereby affecting the function of Rag/raptor/mTOR complex and mTORC1 activity. Furthermore, active Rag GTPases, but not inactive Rag GTPases or raptor rescued the impaired activity and lysosomal localization of mTORC1 in C9orf72‐deficient cells. Taken together, the present study highlights a key role of C9orf72 in lysosomal and autophagosomal regulation, and demonstrates that Rag GTPases and mTORC1 are involved in C9orf72‐mediated autophagy. [ABSTRACT FROM AUTHOR]

Mitophagy controls mitochondrial quality to maintain cellular homeostasis, while aberrations in this process are responsible for neurodegenerative diseases. Mitophagy is initiated through the recruitment of autophagosomes in a ubiquitin-dependent or ubiquitin-independent manner under different stress conditions. Although the detailed molecular mechanisms of how mitophagy processes influence neurodegeneration remain largely uncharacterized, there is mounting evidence indicating that non-coding RNAs (ncRNAs), a variety of endogenous regulators, including microRNAs and long non-coding RNAs, extensively participate in mitophagy processes and play pivotal roles in the aging process and neurodegenerative diseases. Here, we reviewed the major mitophagy pathways modulated by some classical and newly found ncRNAs and summarized the diverse mechanisms in a regulatory network. We also discussed the generalizability of ncRNAs in the development of common neurodegenerative diseases related to proteotoxicity and the importance of mitophagy in the pathogenesis of these diseases. In summary, we propose that ncRNAs act as linkers between mitophagy and neurodegeneration, showing the potential therapeutic application of mitophagy regulation mediated by ncRNAs in neurodegenerative diseases. • Non-coding RNAs modulate diverse mitophagy pathways individually or collectively in a regulatory network. • Non-coding RNAs participate in the progress of multiple neurodegenerative diseases associated with proteotoxicity. • Non-coding RNAs link mitophagy with neurodegeneration, showing a potential therapeutic role in neurodegenerative diseases. [ABSTRACT FROM AUTHOR]