Mfn2 induces NCLX-mediated calcium release from mitochondria.

Kolitsida, P.; Saha, A.; Caliri, A. W.; Assali, E.; Riera, A. M.; Itskanov, S.; Magana, C. S.; Stork, B.; Shirihai, O. S.; Sekler, I.; Koehler, C. M.; van der Bliek, A. M.

doi:10.1101/2024.08.05.606704

bioRxiv · 10.1101/2024.08.05.606704

Mfn2 induces NCLX-mediated calcium release from mitochondria.

Kolitsida, P.·Saha, A.·Caliri, A. W.·Assali, E.·Riera, A. M.·Itskanov, S.·Magana, C. S.·Stork, B.·Shirihai, O. S.·Sekler, I.·Koehler, C. M.·van der Bliek, A. M.

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Abstract

Mfn2 is a mitochondrial outer-membrane fusion protein that also functions as a tether between mitochondria and the ER. Here, we identify a previously unrecognized role for Mfn2 in promoting mitochondrial Ca2+ release via the Na+/Ca2+ exchanger NCLX. This function was uncovered through studies with the fungal toxin phomoxanthone A (PXA), which induces NCLX-dependent Ca2+ release by directly targeting Mfn2. Mfn2-dependent Ca2+ release through NCLX is similarly triggered by ROS in respiring cells treated with oligomycin or mitoPQ. ROS enhances Ca2+ release by strengthening the interaction between Mfn2 and NCLX, an interaction that also requires the mitochondrial outer-membrane protein SLC25A46. Together, these proteins coordinate mitochondrial fission and Ca2+ release to initiate mitophagy. The antioxidant N-acetylcysteine blocks ROS-induced mitochondrial fission, but inhibition of Ca2+ release with the NCLX inhibitor CGP37157 does not, indicating that ROS-driven fission is independent of Ca2+ release. In contrast, Ca2+ release is required for efficient mitophagy, as NCLX inhibition arrests this process at a later stage. We further show that Ca2+ promotes mitophagy through NEDD4-1, which is a Ca2+-responsive E3 ubiquitin ligase. Together, these findings connect mitochondrial ROS production to Ca2+ signaling, mitochondrial remodeling, and mitophagy, providing new insight into how mitochondrial dysfunction may contribute to neurodegenerative and metabolic disease.

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Kolitsida, P., Saha, A., Caliri, A. W., Assali, E., Riera, A. M., Itskanov, S., Magana, C. S., Stork, B., Shirihai, O. S., Sekler, I., Koehler, C. M., van der Bliek, A. M.. 2024-08-06. Mfn2 induces NCLX-mediated calcium release from mitochondria.. https://doi.org/10.1101/2024.08.05.606704

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