Mitochondrial ROS Production at Complexes I and III in Human Myocardium and Skeletal Muscle: A Distinct Pattern...

Prior research has shown that mitochondrial ROS are involved in heart disease and signaling. Most studies use rodent models, leaving uncertainty about human-specific patterns. Human tissues may differ in ROS production mechanisms. Rat tissues often show higher ROS levels than expected in humans. This gap motivated direct comparison of human and rat tissues. No prior work had resolved the exact role of complexes I and III in human myocardium. The assumption that rodent findings apply to humans may limit clinical translation. This study addresses the need for human-specific data on ROS production.

The aim is to compare ROS production at complexes I and III in human and rat tissues. This study focuses on myocardial and skeletal muscle biopsies. Researchers sought to identify dominant ROS-producing sites in humans. They tested whether rat-derived data accurately reflect human physiology. The motivation lies in explaining failed clinical translation of ROS-targeted therapies. Human tissues may have unique redox characteristics. This work clarifies species-specific differences in mitochondrial function. The findings may guide more effective cardioprotective strategies.

The study used human and rat myocardial and skeletal muscle biopsies. ROS production was measured via hydrogen peroxide quantification with Amplex UltraRed. Mitochondrial respiration was monitored using a Clark-type oxygen electrode. Complex I and III activity was assessed under reverse and forward electron transport. Experimental conditions were identical for human and rat tissues. No cultured cells were used—only fresh biopsies. Respiratory rates were normalized to compare ROS production per unit activity. This approach ensured direct comparison between species.

Rat tissues produced more ROS than human tissues under identical conditions. Human tissues showed higher ROS production during reverse electron transport at complex I. Rat tissues primarily generated ROS at complex III. Normalized to respiration, human complex I had higher ROS output than complex III. Rat complex III produced significantly more ROS than complex I. Human complex III showed markedly lower ROS generation than rat complex III. These findings suggest species-specific differences in redox regulation. The results may explain why rodent-based therapies fail in human trials.

The authors propose that human and rat tissues differ in ROS-producing sites. Human complex I dominates under reverse electron transport. Rat complex III is the primary source of ROS. These differences may affect clinical translation of cardioprotective strategies. The findings suggest that human-specific mechanisms are critical for therapy design. No prior work had resolved this distinction in human myocardium. The study does not claim generalizability beyond the tested tissues. The results may inform future research on human mitochondrial redox physiology.