Mitochondria-targeting ACSL6 variant drives mitochondrial fragmentation potentially through local DHA-CoA production

Fatty acids are metabolized into fatty acid-coenzyme A (CoA) by the acyl-CoA synthetase (ACS). Acsl6 is an ACS that preferentially uses polyunsaturated fatty acids such as docosahexaenoic acid (DHA) as substrates. Acsl6 is essential for maintaining normal brain function, visual function, and male fertility. The enzymatic activities of Acsl6 isoforms harboring distinct fatty acid gate-domain motifs differ. However, no studies have comprehensively analyzed the differences in the expression profiles of Acsl6 variants in various tissues. We determined the relative expression levels of the Acsl6 variants in tissues and identified Acsl6-short as the dominant isoform expressed in the brain, retina, and testes. The Acsl6-short is exclusively localized to the mitochondria when transiently expressed in HeLa cells. DHA treatment dynamin-related protein 1 (Drp1)/Mid49/Mid51-dependently induced mitochondrial fragmentation in Acsl6-short-overexpressing HeLa cells. These results suggested that the mitochondrial fragmentation was induced via the local production of DHA-CoA by the Acsl6-short expressed in the mitochondria.