Cardiolipin deficiency disrupts electron transport chain and drives steatohepatitis
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a progressive disorder marked by lipid accumulation, leading to metabolic dysfunction-associated 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…
Metabolic dysfunction-associated steatotic liver disease (MASLD) evolves into metabolic dysfunction-associated steatohepatitis (MASH) due to oxidative stress, which stems from impaired mitochondrial oxidative phosphorylation. Researchers have discovered that alterations in the lipid composition of the inner mitochondrial membrane directly trigger electron transfer inefficiency, thereby promoting oxidative stress.
In humans and mice, a decrease in mitochondrial cardiolipin, a crucial lipid, is observed with MASLD/MASH. In particular, the knockout of hepatocyte-specific CL synthase gene leads to spontaneous and severe MASH with a pronounced steatotic and fibrotic phenotype. Interestingly, the loss of CL boosts mitochondrial respiratory capacity, yet it also facilitates electron leakage mainly at sites III QO and II F of the electron transport chain.
This disruption also leads to a decrease in the formation of the I + III 2 + IV respiratory supercomplex and alters coenzyme Q's propensity to become reduced. Consequently, reduced mitochondrial cardiolipin disrupts the electron transport chain, instigates oxidative stress, and contributes to the development of MASH.
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