Preprint: mutant SOD1 disrupts mitochondrial import machinery in yeast ALS model

A preprint posted to bioRxiv (Cold Spring Harbor Laboratory, 2026-06-06) describes a previously unreported interaction between mutant superoxide dismutase 1 (SOD1) — the protein most commonly implicated in familial amyotrophic lateral sclerosis (fALS) — and the TIM23 complex, a core component of the mitochondrial presequence translocase machinery responsible for importing proteins into the mitochondrial inner membrane.

Using Saccharomyces cerevisiae as a model organism, the authors report that several ALS-associated SOD1 mutants interact with the TIM23 complex via the intermembrane space (IMS) domain of TIM23. In cells expressing these mutants, both the binding affinity and the expression levels of TIM23 complex subunits were reduced, consistent with impaired mitochondrial protein import and downstream organellar dysfunction. The authors propose that this "moonlighting" role — a term used in cell biology to describe a protein performing a secondary function distinct from its canonical activity — may help explain why SOD1 mutations preferentially impair mitochondrial health in ALS.

The work is not peer-reviewed and the findings have not yet been replicated in mammalian models or human cell lines. Yeast-to-human translation of mitochondrial biology requires caution; the TIM23 complex is broadly conserved but the cellular context of motor neuron disease is not recapitulated in yeast. Researchers working on neurodegeneration, mitochondrial disease, or the cell biology of protein import may find the mechanistic hypothesis of interest. Educators may note this as an illustration of how surrogate model organisms are used to dissect protein–complex interactions in rare heritable diseases.