Mitochondrial adenylate kinase 4 regulates dual AMPK and mTORC1 activation

In order to maintain cellular homeostasis, mitochondria integrate bioenergetic, metabolic, and redox cues. Signals both converge on and emanate from mitochondria to respond to varied cellular stressors. Therefore, mitochondrial proteins must play critical roles in maintaining cellular homeostasis. In a search for mitochondrial proteins that impact cellular bioenergetics, we identified the adenylate kinase, AK4, as the most potent regulator of ATP levels out of >1,000 mitochondrial proteins. We also found AK4 expression to significantly impact AMKP and mTORC1 activation status as well as cells' ability to respond to energetic stressors. Suppressing AK4 expression increases steady‐state cellular ATP levels by up to 30%, alters cellular respiration metabolite pools, and results in concomitant activation of both AMPK and mTORC1 signaling. Together, these effects of suppressed AK4 expression allow cells to thrive in the context of nutrient deprivation‐induced stress. The profound effects of AK4 expression on bioenergetics, survival under stress, and dual activation of the AMPK and mTORC1 energy sensing pathways position AK4 as a potential master regulator of mitochondria‐dependent cellular homeostasis. Support or Funding Information NIH 1R15GM123382 CSUPERB New Investigator Grant This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .