Loss of <scp>STARD7</scp> Impairs Mitochondrial Phospholipid Homeostasis and Contributes to Mitochondrial Myopathy

ABSTRACT Mitochondria are composed of phospholipid bilayers rich in phosphatidylcholine (PC). StAR‐related lipid transfer domain‐containing protein 7 (STARD7) functions as a lipid transfer protein that plays a crucial role in maintaining mitochondrial PC homeostasis. In this study, we investigated the physiological role of STARD7 in skeletal muscle using muscle‐specific knockout (mKO) mice. STARD7 expression was markedly higher in the soleus, a mitochondria‐dense slow‐twitch muscle, compared with fast‐twitch fibers. Although muscle fibers from mKO mice exhibited no apparent structural abnormalities, their endurance exercise capacity was markedly reduced. RNA‐seq analysis revealed suppressed expression of fast‐twitch‐related genes accompanied by a reduction in fast‐twitch fibers. At the mitochondrial level, respiratory chain complexes remained intact, but oxygen consumption was consistently decreased. Targeted lipidomic analysis showed decreased levels of PC, cardiolipin (CL), and coenzyme Q in mKO mitochondria, particularly in the soleus. Conversely, expression of CL biosynthetic enzymes was unchanged, and an in vitro binding assay indicated that STARD7 preferentially transfers linoleic acid‐containing PC required for CL remodeling. Furthermore, electron microscopy revealed disorganized cristae structures, whereas 4‐HNE‐modified proteins, mtDNA content, and OPA1 processing remained unaffected. Together, these findings demonstrate that STARD7 plays an essential role in maintaining mitochondrial integrity and function in skeletal muscle, and its loss likely contributes to the pathogenesis of mitochondrial myopathy.