Increased Mitochondrial ROS Generation from Complex III Causes Mitochondrial Damage and Increases Endoplasmic Reticulum Stress

Abstract

RationaleMitochondrial dysfunction contributes to greater susceptibility to injury from superimposed disease in the aged heart. Aging decreases complex III activity and increases ROS production from complex III. Oxidative stress from mitochondria can trigger endoplasmic reticulum (ER) stress.ObjectiveTo study the contribution to additional mitochondria dysfunction and ER stress from Complex III generated ROS.MethodsAntimycin A (AA) (0.4mg/kg i.p.), a complex III inhibitor that increases ROS, was given to adult C57/bl/6 mice and function (echo), mitochondria function and ER stress assessed after 48 hrs.ResultsLow dose in vivo AA led to only mild cardiac dysfunction and no inhibition of respiration through complex III (succinate respiration). AA decreased complex I activity and respiration (glutamate+malate). ER stress increased shown by greater CHOP (transcription factor C/EBP homologous protein) expression (Figure). Susceptibility to mitochondria permeability transition pore (PTP) opening was increased as shown by decreased calcium retention capacity.ConclusionIncreased ROS from complex III damages complex I and increases ER stress with greater PTP susceptibility, mechanisms of enhanced injury observed in the aged heart with superimposed disease including ischemia and reperfusion.Support or Funding InformationThis work was supported by the Office of Research and Development, Medical Research Service Merit Review Award (2IO1BX001355‐01A2) and Department of Veterans Affairs (EJL); National Institutes of Health NIH R21AG054975‐01 (QC). Vechile(n=6) AA(n=5) Cardiac output/beat (ul) 40±2 29±2* Oxidative phosphorylation (nAO/min/mg protein) Glutamate+malate 388±14 332±10* Succinate 531±32 538±20 Complex I (mU/mg protein) 841±61 612±38* Calcium Retention Capacity (nmol calcium/mg protein) 1033±56 848±52* Mean ± SEM: p<0.05 vs. Vechicle. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.