Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a progressive disorder marked by lipid accumulation, leading to steatohepatitis (MASH). A key feature of the transition to MASH involves oxidative stress resulting from defects in mitochondrial oxidative phosphorylation (OXPHOS). Here, we show that pathological alterations in the lipid composition of the inner mitochondrial membrane (IMM) directly instigate electron transfer inefficiency to promote oxidative stress. Specifically, mitochondrial cardiolipin (CL) was downregulated with MASLD/MASH in mice and in humans. Hepatocyte-specific CL synthase knockout (CLS-LKO) led to spontaneous and robust MASH with extensive steatotic and fibrotic phenotype. Loss of CL paradoxically increased mitochondrial respiratory capacity but also reduced the formation of I+III2+IV1 respiratory supercomplex and interfered with the ability of coenzyme Q (CoQ) to transfer electrons to complex III. In turn, the bottleneck at complex III promoted electron leak primarily at site IIIQ0 as well as other upstream sites in the electron transport chain. Thus, reduction in mitochondrial CL promotes oxidative stress and contributes to pathogenesis of MASH.