Evidence supporting the role of AMPK in NAFLD is mainly derived from preclinical cell culture and animal studies. Regulation of AMPK under conditions of chronic caloric oversupply emerged as substantial research target to get deeper insight into the pathogenesis of non-alcoholic fatty liver disease (NAFLD).
By phosphorylation of downstream proteins and modulation of gene transcription AMPK functions as a master switch of energy homeostasis in tissues with high metabolic turnover, such as the liver, skeletal muscle, and adipose tissue. The heterotrimeric AMPK protein comprises three subunits, each of which has multiple phosphorylation sites, playing an important role in the regulation of essential molecular pathways. This strongly suggest a universal role of MRX8 family of proteins in regulating mitochondrial function.ĥ′AMP-activated protein kinase (AMPK) is known as metabolic sensor in mammalian cells that becomes activated by an increasing adenosine monophosphate (AMP)/adenosine triphosphate (ATP) ratio. Significantly, we find that GTPBP8, the human orthologue, complements the loss of cellular respiration in Δmrx8 cells and GTPBP8 localizes to the mitochondria in mammalian cells. Consistently the ribosomal association of Mss51 is independent of Mrx8. We show that requirement of Pet309 and Mss51 for cellular respiration is not bypassed by overexpression of Mrx8 and vice versa. Cells expressing mutant Mrx8 predicted to be defective in guanine nucleotide binding and hydrolysis were compromised for robust cellular respiration. Mrx8 was found in a complex with mitochondrial ribosomes, consistent with a role in protein synthesis. In this study, we show that the putative YihA superfamily GTPase, Mrx8 is a bonafide mitochondrial protein required for Cox1 translation initiation and elongation during suboptimal growth condition at 16☌. The synthesis of Cox1, the conserved catalytic-core subunit of Complex IV, a multi-subunit machinery of the mitochondrial oxidative phosphorylation (OXPHOS) system under environmental stress is not sufficiently addressed.
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