Novel interactions between the <scp>C5</scp> ‐ <scp>C5aR</scp> 1 Axis and <scp>IF</scp> 1: Implications for kidney mitochondrial physiology and ischemia–reperfusion injury

Abstract Ischemia‐reperfusion injury (IRI) is a prevalent condition that predominantly afflicts hospitalized patients, inducing acute kidney injury (AKI). In recent years, complement 5 (C5) and its anaphylatoxin receptor C5aR1 have been implicated in driving kidney IRI and loss of function. Beyond this, prior studies suggest C5‐C5aR1 mediates mitochondrial ROS production, although its role in the mitochondria has never been fully characterized. Here, we leverage a previously generated model of C5 gene deletion (male C5 −/− rats) and the clinically relevant C5aR1 inhibitor Avacopan (AV) to investigate C5‐C5aR1 signaling in renal mitochondrial physiology and pathophysiology. For the first time, we report that C5‐C5aR1 axis inhibition modifies physiological mitochondrial protein levels, respiratory activity, and complexes/supercomplexes. We identified a novel relationship between the C5‐C5aR1 axis and ATPase Inhibitory Factor 1 (IF1), a potent regulator of the ATP synthase, using in vivo and in vitro approaches. Post‐IRI, C5‐C5aR1 axis inhibition improved kidney function/morphology and preserved ATP levels, despite IRI‐mediated disintegration of mitochondrial complexes and supercomplexes. We show in vitro that C5‐C5aR1 axis inhibition facilitated IF1‐dependent ATP recovery via the glycolysis pathway. Collectively, our results demonstrate a complex interplay between C5‐C5aR1 and IF1 in renal mitochondria, which contributes to mitochondrial pathophysiology during IRI.