Mitochondrion: I am more than a fuel server

Mitochondria are unique cytoplasmic organelles faithfully generating fuel to support healthy living and carrying out normal metabolic function (1). Mitochondria possess their own DNA (mtDNA), strictly follow maternal inheritance and are integral part of the oxidative phosphorylation system (OXPHOS) in producing cellular ATP (1). They are the central regulators of OXPHOS system and constituted of five respiratory complexes (complex I-V) which are assembled from multiple polypeptides, some encoded by mtDNA and others by nuclear DNA (nDNA). The human mtDNA is a 16.5-kb double stranded closed circular molecule, which encodes 12S and 16S rRNAs, 22 tRNAs and 13 proteins essential for the mitochondrial respiratory complex (1) (Figure 1). Remarkably, intracellular and intercellular mitochondrial heterogeneity exist and each mitochondrion contain hundreds of copies of mtDNA and nearly all of these mtDNA copies remains identical or homoplasmic at birth. Notably, due to the lack of protective histones, rate of mutation in mtDNA is approximately 10 times higher than the nuclear DNA (nDNA) and comparatively easier to spot due to the high copy number particularly in the malignant cells. It is overwhelming to think from the evolutionary perspective about the retention of 13 mtDNA encoded proteins in the mitochondria, while more than 1,500 molecules are traveling from the nucleus to orchestrate diversified mitochondrial function efficiently