Mitochondrial depolarization stabilizes the vitamin B12 chaperone MMADHC in the cytosol to increase MTR activity

• 成果类型: Article
• 署名作者: Rath, Sneha P.; Li, Zhu; Guha, Arkajit; Dong, Fangcong; Banerjee, Ruma; Mootha, Vamsi K.
• 署名单位: Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard University; Harvard Medical School; University of Michigan System; University of Michigan
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2537797123
• 发表日期: 2026-09-15
• 页码: e2537797123
• 关键词: proton motive force; mitochondria; methionine synthase; MMADHC; vitamin B-12; protein; import; prediction; proteomics; pink1

摘要

Of the similar to 1,100 mitochondrial proteins, only a handful like PINK1 and ATFS-1 are known to stabilize and relocalize upon collapse of the proton motive force (PMF) to execute signaling roles. To systematically identify genes that increase exclusively at the protein level upon PMF collapse, we performed a joint proteomic and RNA-seq screen. The screen revealed 10 candidates (six mitochondrial), including two genes in vitamin B-12 metabolism -the B-12 chaperone MMADHC and cytosolic B-12-dependent 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR). MMADHC is short-lived across cell types and we show that its levels increase with PMF collapse. MMADHC stabilization precedes PINK1 activation in a time course of increasing mtDNA depletion, suggesting greater sensitivity to PMF collapse. MMADHC accumulates in mitochondria with LONP1 inhibition but in the cytosol upon PMF collapse, likely due to mitochondrial import failure. Cytosol-stabilized MMADHC increases MTR levels and activity. Altogether, the mitochondrial PMF regulates the cytosolic B-12-dependent MTR, integral to one-carbon metabolism, by controlling the stability and compartmentalization of the B-12 chaperone MMADHC.