A pair of transporters controls mitochondrial Zn2+ 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.