A pair of transporters controls mitochondrial Zn2+ levels to maintain mitochondrial homeostasis

Abstract

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.

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“…Moreover, SLC-25A25/SCaMC-2 was identified as an important regulator of mitochondrial Zn 2+ import, the losing of which suppresses functional and structural defects caused by a loss of SLC-30A9. It was shown that mitochondria mostly import Zn 2+ from the endoplasmic reticulum Zn 2+ pool [29]. Similarly, the role of SLC-30A9 in Zn 2+ export from mitochondria was also confirmed in humans, where loss of SLC-30A9 leads to excessive Zn 2+ accumulation in mitochondria, severe mitochondrial swelling, increased ROS production and dysregulated metabolic function.…”

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“…In addition, the target site of the steroid 1,3,4-oxadiazole was demonstrated to be the mitochondria and nucleus in the midgut tissues of Eriosoma lanigerum [ 49 ]. Mitochondria are the powerhouses of the cell and mitochondrial dysfunction is related to oxidative homeostasis and lipid and energy metabolism [ 50 , 64 ]. For example, zebrafish exposed to triazoles had impaired mitochondrial oxidative phosphorylation and oxidative stress as well as dysregulation of lipid metabolism, which resulted in developmental disorders and movement disorders [ 64 ].…”

“…Sample preparation was the same as that described above. A previous method was modified as appropriate [ 47 , 48 , 49 , 50 ]. Samples were fixed overnight at 4 °C using 2.5% glutaraldehyde in 0.1 M PB (pH 7.4).…”

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“…Further still the zinc transporters Zip7 and ZnT7 have also been shown to have dual localization in mitochondria and ER and expression of Zip7 and ZnT7 contribute to cellular zinc exchange between the organelles in certain cell types ( Tuncay et al, 2019 ). Finally Znt9 (SLC30A9) was identified as a zinc exporter in mitochondria ( Deng et al, 2021 ) and SLC25A25 has been implicated in at least regulating uptake of zinc as deletion can reverse phenotypes induced by SLC30A9 deletion ( Ma et al, 2022 ). Perhaps redundancy is the reason for the failure of the yeast genetic screens to yield a single candidate.…”