近日，美国达特茅斯学院Henry N. Higgs课题组发现，脂肪酸酰辅酶A通过MiD49和MiD51的寡聚激活线粒体分裂。相关论文于2024年4月9日在线发表在《自然—细胞生物学》杂志上。

研究人员表明，长链酰基辅酶A（LCACA）通过诱导两种相关的线粒体分裂蛋白MiD49和MiD51的寡聚化，激活了它们刺激DRP1 GTPase的能力。寡聚体中LCACA与MiD的比例为1:1，这表明它们在之前确定的核苷酸结合口袋中发生了相互作用，而该口袋中的点突变会减少LCACA与MiD51的结合以及LCACA诱导的寡聚。在细胞中，这种LCACA结合突变体不能在线粒体上组装成点状，也不能挽救MiD49/51基因敲除对线粒体长度和DRP1招募的影响。

此外，用BSA结合的油酸进行细胞处理会导致LCACA增加，从而以MiD49/51依赖性的方式促进线粒体分裂。这些结果表明，LCACA是MiD的内源性配体，可诱导线粒体分裂，并提供了脂肪酸诱导线粒体分裂的潜在机制。最后，在DRP1激活过程中，MiD49或MiD51寡聚体与Mff而不是与肌动蛋白丝协同作用，这表明DRP1激活有不同的途径。

研究人员表示，线粒体裂变发生在许多细胞过程中，但对分裂的调控却知之甚少。

附：英文原文

Title: Fatty acyl-coenzyme A activates mitochondrial division through oligomerization of MiD49 and MiD51

Author: Liu, Ao, Kage, Frieda, Abdulkareem, Asan F., Aguirre-Huamani, Mac Pholo, Sapp, Gracie, Aydin, Halil, Higgs, Henry N.

Issue&Volume: 2024-04-09

Abstract: Mitochondrial fission occurs in many cellular processes, but the regulation of fission is poorly understood. We show that long-chain acyl-coenzyme A (LCACA) activates two related mitochondrial fission proteins, MiD49 and MiD51, by inducing their oligomerization, which activates their ability to stimulate the DRP1 GTPase. The 1:1 stoichiometry of LCACA:MiD in the oligomer suggests interaction in the previously identified nucleotide-binding pocket, and a point mutation in this pocket reduces LCACA binding and LCACA-induced oligomerization for MiD51. In cells, this LCACA binding mutant does not assemble into puncta on mitochondria or rescue MiD49/51 knockdown effects on mitochondrial length and DRP1 recruitment. Furthermore, cellular treatment with BSA-bound oleic acid, which causes increased LCACA, promotes mitochondrial fission in an MiD49/51-dependent manner. These results suggest that LCACA is an endogenous ligand for MiDs, inducing mitochondrial fission and providing a potential mechanism for fatty-acid-induced mitochondrial division. Finally, MiD49 or MiD51 oligomers synergize with Mff, but not with actin filaments, in DRP1 activation, suggesting distinct pathways for DRP1 activation.

DOI: 10.1038/s41556-024-01400-3

Source: https://www.nature.com/articles/s41556-024-01400-3