Zn²⁺ 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 Zn²⁺ 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 Zn²⁺. We demonstrate that SLC-30A9/ZnT9 is a mitochondrial Zn²⁺ exporter. Loss of SLC-30A9 leads to mitochondrial Zn²⁺ 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 Zn²⁺ import. Loss of SLC-25A25 suppresses the abnormal mitochondrial Zn²⁺ accumulation and defective mitochondrial structure and functions caused by loss of SLC-30A9. Moreover, we reveal that the endoplasmic reticulum contains the Zn²⁺ pool from which mitochondrial Zn²⁺ is imported. These findings establish the molecular basis for controlling the correct mitochondrial Zn²⁺ levels for normal mitochondrial structure and functions.

Zn ²⁺是许多线粒体蛋白活性所必需的，可调节线粒体动力学、细胞凋亡和线粒体自噬。然而，尚不清楚如何达到适当的线粒体 Zn ²⁺水平以维持线粒体稳态。利用秀丽隐杆线虫，我们在此揭示了一对线粒体定位转运蛋白控制着线粒体的 Zn ²⁺水平。我们证明 SLC-30A9/ZnT9 是线粒体 Zn ²⁺输出蛋白。 SLC-30A9 的缺失会导致线粒体 Zn ²⁺积累，从而损害线粒体，损害动物发育并缩短寿命。我们进一步确定 SLC-25A25/SCaMC-2 是线粒体 Zn ²⁺输入的重要调节因子。 SLC-25A25 的缺失会抑制线粒体 Zn ^{2+ 的}异常积累以及因 SLC-30A9 的缺失而导致的线粒体结构和功能缺陷。此外，我们揭示内质网含有Zn ²⁺库，线粒体Zn ²⁺是从该库中输入的。这些发现为控制正常线粒体结构和功能的正确线粒体 Zn ²⁺水平奠定了分子基础。