PT  - JOURNAL ARTICLE
AU  - Felix Straub
AU  - Tobias Welz
AU  - Hannah Alberico
AU  - Rafael Oliveira Brandão
AU  - Anna Huber
AU  - Annette Samol-Wolf
AU  - Cord Brakebusch
AU  - Dori Woods
AU  - Martin Kollmar
AU  - Javier Martin-Gonzalez
AU  - Eugen Kerkhoff
TI  - The SPIRE1 actin nucleator coordinates actin/myosin functions in the regulation of mitochondrial motility
AID  - 10.1101/2020.06.19.161109
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.06.19.161109
4099  - http://biorxiv.org/content/early/2020/06/20/2020.06.19.161109.short
4100  - http://biorxiv.org/content/early/2020/06/20/2020.06.19.161109.full
AB  - Subcellular localisation of mitochondria provides a spatial and temporal organisation for cellular energy demands. Long-range mitochondrial transport is mediated by microtubule tracks and associated dynein and kinesin motor proteins. The actin cytoskeleton has a more versatile role and provides transport, tethering, and anchoring functions. SPIRE actin nucleators organise actin filament networks at vesicle membranes, which serve as tracks for myosin 5 motor protein-driven transport processes. Following alternative splicing, SPIRE1 is targeted to mitochondria. In analogy to vesicular SPIRE functions, we have analysed whether SPIRE1 regulates mitochondrial motility. By tracking mitochondria of living fibroblast cells from SPIRE1 mutant mice and splice-variant specific mitochondrial SPIRE1 knockout mice, we determined that the loss of SPIRE1 function increased mitochondrial motility. The SPIRE1 mutant phenotype was reversed by transient overexpression of mitochondrial SPIRE1, which almost completely inhibited motility. Conserved myosin 5 and formin interaction motifs contributed to this inhibition. Consistently, mitochondrial SPIRE1 targeted myosin 5 motors and formin actin filament generators to mitochondria. Our results indicate that SPIRE1 organises an actin/myosin network at mitochondria, which opposes mitochondrial motility.Summary statement The mitochondrial SPIRE1 protein targets myosin 5 motor proteins and formin actin-filament nucleators/elongators towards mitochondria and negatively regulates mitochondrial motility.