Albumosomes formed by cytoplasmic pre-folding albumin maintain mitochondrial homeostasis and inhibit nonalcoholic fatty liver disease

Hepatic mitochondrial dysfunction contributes to the progression of nonalcoholic fatty liver disease (NAFLD). However, the factors that maintain mitochondrial homeostasis, especially in hepatocytes, are largely unknown. Hepatocytes synthesize various high-level plasma proteins, among which albumin is most abundant. In this study, we found that pre-folding albumin in the cytoplasm is completely different from folded albumin in the serum. Mechanistically, endogenous pre-folding albumin undergoes phase transition in the cytoplasm to form a shell-like spherical structure, which we call the albumosome. Albumosomes interact with and trap pre-folding carnitine palmitoyltransferase 2 (CPT2) in the cytoplasm. Albumosomes control the excessive sorting of CPT2 to the mitochondria under high-fat-diet-induced stress conditions; in this way, albumosomes maintain mitochondrial homeostasis from exhaustion. Physiologically, albumosomes accumulate in hepatocytes during murine aging and protect the livers of aged mice from mitochondrial damage and fat deposition. Morphologically, mature albumosomes have a mean diameter of 4 mu m and are surrounded by heat shock protein Hsp90 and Hsp70 family proteins, forming a larger shell. The Hsp90 inhibitor 17-AAG promotes hepatic albumosomal accumulation in vitro and in vivo, through which suppressing the progression of NAFLD in mice.

Automated summary

Hepatic mitochondrial dysfunction contributes to the progression of NAFLD. This study reveals that albumosome, a shell-like structure formed by pre-folding albumin in the cytoplasm, plays a crucial role in maintaining mitochondrial homeostasis and preventing mitochondrial damage. Albumosomes interact with and trap pre-folding CPT2, controlling its excessive sorting to the mitochondria under high-fat-diet-induced stress conditions. Accumulation of albumosomes in hepatocytes during aging protects the liver from mitochondrial damage and fat deposition.