ROLE OF THE LIPID TRANSPORT PROTEIN STARD7 IN MITOCHONDRIAL STRUCTURE AND MANTAINANCE

ROJAS, MARÍA L.; MUÑOZ, JUAN P.; FLORES MARTIN, JESICA B.; SANCHEZ-FERNANDEZ-DE-LANDA, PAULA; CRUZ DEL PUERTO, MARIANO; GENTI-RAIMONDI, SUSANA; ZORZANO, ANTONIO

Fiuggi

Workshop; Workshop Inter-organelle contacts biology; 2023

EMBO

Mitochondria are dynamic organelles that are crucial for cell function and survival and are implicated in oxidative energy production. Mitochondrial lipids determine mitochondrial membrane architecture, and changes in their composition affect several important functions such as respiratory metabolism, protein import, mitophagy, and mitochondrial dynamics. StarD7 is a member of the START protein family and is required for phosphatidylcholine delivery to the mitochondria. Its deficiency has been associated with an impairment of cellular processes, such as proliferation and migration, and it has also been reported that it is necessary for myogenic differentiation. Here, we show that StarD7 deficiency in C2C12 muscle cells results in the accumulation of abnormal mitochondria with an altered cristae structure, a reduced number of mitochondria per cell area, and a switch in ATP production by glycolysis. In addition, StarD7-deficient cells show an increase in mitochondria-ER contact sites and disturbances in lipid handling, as evidenced by lipid droplet (LD) accumulation. Interestingly, StarD7-deficient cells showed accumulation of mitophagy markers LC3II and BNIP3 in mitochondria-enriched fractions and accumulation of autophagolysosomal and lysosomal vesicles. Furthermore, live-cell imaging experiments of StarD7 knockdown cells expressing mitochondria-targeted mKeima indicated enhanced mitochondrial delivery into lysosomes. Importantly, StarD7 reconstitution in StarD7-deficient cells restored LC3II expression in mitochondria-enriched fractions to levels similar to those observed in control cells. Collectively, these findings suggest that StarD7-deficient C2C12 myoblasts are associated with an increase in mitochondria-ER contacts, disturbances in neutral lipid accumulation and increased mitophagy flux, which may explain the inability of these cells to differentiate into myotubes.