A pair of transporters controls mitochondrial Zn(2+) levels to maintain mitochondrial homeostasis

Zn(2+) is required for the activity of many mitochondrial proteins, which regulate mitochondrial dynamics, apoptosis and mitophagy. However, it is not understood how the proper mitochondrial Zn(2+) level is achieved to maintain mitochondrial homeostasis. Using Caenorhabditis elegans, we reveal here that a pair of mitochondrion-localized transporters controls the mitochondrial level of Zn(2+). We demonstrate that SLC-30A9/ZnT9 is a mitochondrial Zn(2+) exporter. Loss of SLC-30A9 leads to mitochondrial Zn(2+) accumulation, which damages mitochondria, impairs animal development and shortens the life span. We further identify SLC-25A25/SCaMC-2 as an important regulator of mitochondrial Zn(2+) import. Loss of SLC-25A25 suppresses the abnormal mitochondrial Zn(2+) accumulation and defective mitochondrial structure and functions caused by loss of SLC-30A9. Moreover, we reveal that the endoplasmic reticulum contains the Zn(2+) pool from which mitochondrial Zn(2+) is imported. These findings establish the molecular basis for controlling the correct mitochondrial Zn(2+) levels for normal mitochondrial structure and functions. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13238-021-00881-4.