Mitophagy-driven metabolic switch reprograms stem cell fate

Prajna Paramita Naik, Alexander Birbrair, Sujit Kumar Bhutia

"Cellular reprogramming" facilitates the generation of desired cellular phenotype through the cell fate transition by affecting the mitochondrial dynamics and metabolic reshuffle in the embryonic and somatic stem cells. Interestingly, both the processes of differentiation and dedifferentiation witness a drastic and dynamic alteration in the morphology, number, distribution, and respiratory capacity of mitochondria, which are tightly regulated by the fission/fusion cycle, and mitochondrial clearance through autophagy following mitochondrial fission. Intriguingly, mitophagy is said to be essential in the differentiation of stem cells into various lineages such as erythrocytes, eye lenses, neurites, myotubes, and M1 macrophages. Mitophagy is also believed to play a central role in the dedifferentiation of a terminally differentiated cell into an induced pluripotent cell and in the acquisition of 'stemness' in cancer cells. Mitophagy-induced alteration in the mitochondrial dynamics facilitates metabolic shift, either into a glycolytic phenotype or into an OXPHOS phenotype, depending on the cellular demand. Mitophagy-induced rejuvenation of mitochondria regulates the transition of bioenergetics and metabolome, remodeling which facilitates an alteration in their cellular developmental capability. This review describes the detailed mechanism of the process of mitophagy and its association with cellular programming through alteration in the mitochondrial energetics. The metabolic shift post mitophagy is suggested to be a key factor in the cell fate transition during differentiation and dedifferentiation.