LHON is characterized by RGC degeneration and subsequent loss of central vision, predominately in young men.
172 Dombi et al.
173 showed that mtDNA mutation m.13051G>A is associated with increased mitophagy (assessed by LC3 and TOM20 colocalization in addition to mtDNA quantification) in patient-derived fibroblasts with LHON/Leigh phenotypes. The use of idebenone, a synthetic antioxidant similar to coenzyme Q10, reduced mitophagy in the fibroblast cultures and is thought to provide a possible therapeutic effect. Zhang et al.
174 demonstrated reduced LC3II and accumulation of p62 in cybrid mtDNA ND5 12338T>C mutant cells, possibly suggesting decreased autophagy/mitophagy in contrast to the Dombi model, although mitophagic flux was not measured. Of note, the Zhang group's findings occurred despite the cells having reduced ATP, reduced membrane potential, and increased production of ROS. The reduced mitophagy phenotype in LHON is supported by Sharma et al.,
175 who demonstrated that activation of mitophagy in cells harboring LHON mtDNA mutations rescues mitochondrial function and cell survival. Work by Jankauskaitė et al. (2020)
172 and Kodroń et al. (2019)
176 also showed higher mitochondrial mass, lower mitophagic receptor BNIP3, and lower autophagic flux present in LHON lymphoblast cultures treated with testosterone, as well as in cybrid LHON mutation cultures, supporting a reduced mitophagy phenotype in LHON.
172,176 Genome-wide linkage studies have further shown two
PARL SNPs associated with LHON mitochondrial disease.
177 PARL protease is responsible for processing the antiapoptotic form of OPA1, which subsequently prevents the release of mitochondrial cytochrome
c into the cytosol, normally an intrinsic signal initiating apoptosis.
178 Finally, in the
Ndufs4–/– mouse model of LHON, knocking out mir181a/b increased mitophagy, as measured by an increase in the expression of parkin and p62 protein expression, and enhanced mitochondrial biogenesis, as measured by mtDNA quantitative PCR and complex I, II, and IV biochemical activity.
179 Altogether, most evidence suggests that LHON patients have a reduced amount of mitophagy and could therefore benefit from a therapeutic strategy that increases mitophagy.