Mitochondria: The Crossroads of Complement Activation and Kidney Injury Progression

Acute kidney injury, a broad term associated with diverse etiologies, is a common pathological condition that develops into chronic disease via mechanisms that have yet to be fully understood. Key processes that promote chronic disease transition include mitochondrial dysfunction and aberrant complement system activation, specifically inducing inflammation and accumulation of pro-fibrotic changes. Although emerging evidence strongly indicates that these two processes are closely intertwined, identification of appropriate therapeutic targets remains limited. Among complement proteins, terminal portions of the cascade, including complement 5 (C5), exert particularly robust effects on mitochondrial function across tissues, including the kidney. Moreover, C5 is the most terminal portion of the cascade to produce a highly pro-inflammatory anaphylatoxin, positioning C5 as an ideal clinical target during kidney injury/disease. In this review, we will hence summarize current knowledge regarding mitochondrial contributions to kidney pathophysiology through the lens of the close relationship between mitochondria and the complement system, particularly C5.