MondoA as a regulator of cellular senescence and mitochondrial homeostasis

Autophagy (self-degradation mechanism that rids the body of dysfunctional organelles) is a process that is important for homeostasis (maintenance of internal body environment), and its disruption affects general health. Literature has highlighted that autophagic activity is inversely related to aging, where it decreases as the organism gets older; in addition, activation of autophagy was linked with prolonged lifespan and prevention of age-related diseases. For instance, overexpression of autophagy related-genes (Atgs), like Atg5 in mice, was linked to longevity, while suppression of autophagy-negative regulator Rubicon was found to prevent neurodegenerative disorders.

MondoA is a transcription factor that regulates metabolism to detect changes in cellular energy status in the outer mitochondrial membrane. It has been found to play a role in lipid metabolism, insulin resistance, and tumor formation. According to data from previous experiments, MondoA plays a role in autophagy and was found to prolong the lifespan of C. elegans in response to factors like caloric restriction. Yamamoto-Imoto et al. sought to understand the role of MondoA in aging and longevity across different species. In addition, they wanted to elucidate MondoA function as a regulator of autophagy and mitochondrial homeostasis, therefore protecting from cellular senescence.

Results of their study revealed that the decline of the autophagy process accelerates cellular senescence, which was validated in 2 types of human cell lines. Regarding MondoA, the researchers found that retained MondoA activity delays cellular senescence through promoting autophagy. They highlighted that MondoA knockdown enhanced expression of p16, p21, and p53 (proteins involved in cellular senescence) and that its depletion increased senescence. 

Further investigation revealed that disrupting MondoA and knockdown of Prdx3 (Peroxiredoxin-3 is a gene whose products possess antioxidant activity and play a role in mitochondrial homeostasis) resulted in increased expression of several of the aforementioned senescence proteins. In addition, it was highlighted that disruption of MondoA function resulted in increased Rubicon activity, hence reduced autophagy.

To understand the impact of MondoA on cellular senescence in humans, the authors researched human kidney biopsies. They found that cells from aged individuals and those with ischemic kidney injury had lower levels of MondoA compared to those from young and healthy people. The authors highlighted that their findings suggest that MondoA delays cellular senescence by promoting autophagy through suppressing Rubicon and maintaining homeostasis via Prdx3.

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