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. 2021 Apr 5;78(10):4785–4804. doi: 10.1007/s00018-021-03819-5

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© The Author(s) 2021

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 3 — Mitochondrial dysfunction in spinal muscular atrophy. 1. Following mitochondrial stress (e.g., hypoxia), mitochondrial PGAM family member 5 (PGAM5) inhibits Wnt/β-catenin signalling, leading to mitophagy (indirectly determined by mitochondrial membrane potential [MMP]). In addition, cytosolic PGAM activates Wnt/β-catenin signalling, leading to mitochondrial biogenesis (determined by mitochondrial number and mitochondrial DNA [mtDNA] production). This should ensure the removal of dysfunctional mitochondria and concurrent generation of new mitochondria to optimise the mitochondrial population during times of stress. The effect of survival motor neuron (SMN) in this mitochondrial stress pathway is not known but Wnt/β-catenin signalling is a known driver of spinal muscular atrophy (SMA) pathology. 2. Mitochondrial transfer RNAs (tRNAs) are released from the mitochondrial matrix during mitochondrial stress, where they can interact with heterogeneous nuclear ribonucleoprotein (hnRNP)-A1 protein in the cytosol. The downstream effect of this interaction is not known but may involve mitonuclear communication or mitophagy. Alternatively, hypoxia is already known to alter SMN splicing via hnRNP proteins. 3. Ubiquitination of vacuolar protein sorting 13 homolog D (VPS13D) by a ubiquitin-like modifier activating enzyme 1 (UBA1)-mediated mechanism influences mitochondrial size and morphology through fission and fusion mechanisms. 4. HuD and SMN interact to transport mRNAs along the cytoskeleton. HuD has independently been shown to transport mRNA for the mitochondrial fusion protein, mitofusin 2 (MFN2), in pancreatic β cells (a known site of dysfunction in SMA). 5. SMN colocalises with actin-related protein 2 (ARX-2) at mitochondria. Together both proteins are involved in mitochondrial trafficking and distribution. 6. Other SMN interactors (Bcl-2, Tim50) and pathways (stasimon, NCALD) have mitochondrial locations, albeit the direct effect of these proteins and downstream functions (in brackets) has not been determined. Dashed lines indicate pathways that are linked to mitochondrial stress