Age‐Related Loss of Mitochondrial Glutathione Exacerbates Vulnerability to Redox‐Cycling Challenge

Abstract

In order to determine the role of mitochondrial GSH (mGSH) loss in increased susceptibility to xenobiotic insult with age, markers of mitochondrial function were measured in intact and digitonin‐permeabilized hepatocytes from young and old F344 rats under a redox cycling (300 μM menadione) challenge. While the rate of mGSH loss under menadione challenge was similar in both age groups, a 47% decline in initial mGSH levels with age resulted in a 50% loss of mGSH in old rat hepatoctyes versus 28% in young within 10 minutes of exposure. Examination of mitochondrial membrane potential (Δψm), which is acutely regulated by mGSH content, showed a 21% basal loss with age. Additionally, within five minutes of menadione challenge, Δψm in young was not markedly reduced but had collapsed in old rat hepatocytes. Further characterization demonstrated that basal respiration and respiratory reserve capacity, indicators of cellular bioenergetic capacity, were both significantly reduced upon menadione treatment in old rat hepatocytes but not in young. Examination of proton leak, complex I, and complex II contributions to mitochondrial oxygen consumption rates under menadione challenge revealed no marked effect in young rat hepatocytes, while old rat hepatocytes demonstrated a significant loss in complex I activity as well as increases in proton leak and a compensatory increase in complex II activity. These data clearly demonstrate an age‐related increase in mitochondrial susceptibility to a redox‐cycling challenge, particularly in complex I, and provide a plausible mechanism that links this vulnerability to mGSH perturbations.Support or Funding InformationN.T. is supported by an NIH grant. Title: CAM RESEARCH TRAINING IN NEUROSCIENCE & STRESS; number: 2T32AT002688.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.