A dosage-sensitive ALLO-1 network coordinates mitochondrial quality control to enable functional recovery of structurally compromised muscle

Abstract

Functional recovery of muscle can precede structural repair, yet the mechanisms enabling this dissociation remain elusive. In C. elegans, unc-45(m94) mutants recover motility after heat-induced paralysis despite persisting sarcomeric disorganisation, offering a model to dissect non-contractile drivers of early recovery. Quantitative proteomics identified ALLO-1, a selective autophagy adaptor previously characterised for mediating paternal mitochondrial elimination during embryogenesis, as strongly upregulated during the recovery phase. Proteomic and genetic analyses further revealed a network of ALLO-1-associated factors, including the kinase IKKE-1 (a known ALLO-1 activator), SIP-1 (a small heat shock protein), DIM-1 (a sarcomeric tether), and CAR-1 (an ER-associated RNA-binding protein). In adult muscle, ALLO-1 restrains mitophagy to preserve mitochondrial integrity. Its depletion triggers mitochondrial fragmentation and excessive turnover, especially in the sensitised unc-45(m94) background. Overexpression suppresses mitophagy but reduces oxidative capacity, revealing a dosage-sensitive checkpoint. While IKKE-1 and SIP-1 promote mitochondrial stability, DIM-1 and CAR-1 facilitate turnover when ALLO-1 levels fall below threshold. Together, this regulatory module integrates proteostatic, translational, and mechanical signals to safeguard mitochondrial homeostasis and enable recovery when contractile architecture is compromised.