Novel interactions between the C5-C5aR1 Axis and IF1: Implications for kidney mitochondrial physiology and...

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.