Adenine nucleotide translocase: Current knowledge in post‐translational modifications, regulations and pathological implications for human diseases

Adenine nucleotide translocases (ANTs) are central to mitochondrial integrity and bioenergetic metabolism. This review aims to integrate the progresses and knowledge on ANTs over the last few years, contributing to a potential implication of ANTs for various diseases. Structures, functions, modifications, regulators and pathological implications of ANTs for human diseases are intensively demonstrated here. ANTs have four isoforms (ANT1-4), responsible for exchanging ATP/ADP, possibly composing of pro-apoptotic mPTP as a major component, and mediating FA-dependent uncoupling of proton efflux. ANT can be modified by methylation, nitrosylation and nitroalkylation, acetylation, glutathionylation, phosphorylation, carbonylation and hydroxynonenal-induced modifications. Compounds, including bongkrekic acid, atractyloside calcium, carbon monoxide, minocycline, 4-(N-(S-penicillaminylacetyl)amino) phenylarsonous acid, cardiolipin, free long-chain fatty acids, agaric acid, long chain acyl-coenzyme A esters, all have an ability to regulate ANT activities. ANT impairment leads to bioenergetic failure and mitochondrial dysfunction, contributing to pathogenesis of diseases, such as diabetes (deficiency), heart disease (deficiency), Parkinson's disease (reduction), Sengers Syndrome (decrease), cancer (isoform shifting), Alzheimer's Disease (coaggregation with Tau), Progressive External Opthalmoplegia (mutation), and Fascioscapulohumeral muscular dystrophy (overexpression). This review improves the understanding of the mechanism of ANT in pathogenesis of human diseases, and opens a window for novel therapeutic strategies targeted on ANT in diseases.