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This study reveals that MSTO1, a protein whose mutations cause mitochondrial diseases, functions as an assembly factor for TRiC, an essential cytosolic chaperone. Using rapid protein depletion techniques, researchers found that loss of MSTO1 causes TRiC levels to decrease before mitochondrial fragmentation occurs, and that TRiC reduction alone is sufficient to cause the mitochondrial defects seen in MSTO1-deficient cells. The findings establish a previously unknown link between cytosolic protein quality control machinery and mitochondrial health, suggesting that MSTO1-related diseases may result from impaired TRiC assembly rather than direct effects on mitochondria.
Why it matters
This work fundamentally changes our understanding of how MSTO1 mutations cause disease, pointing to disrupted cytosolic protein folding rather than direct mitochondrial dysfunction as the primary defect. These insights could lead to new therapeutic strategies targeting protein quality control pathways for treating mitochondrial diseases associated with MSTO1 mutations, including certain forms of ataxia and muscular dystrophy.
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⚠️ Preprint – Noch nicht peer-reviewed
Dieser Artikel wurde noch nicht von unabhängigen Experten begutachtet. Die Ergebnisse sind vorläufig und sollten mit Vorsicht interpretiert werden.
Bi-allelic mutations in MSTO1 are linked to clinical disease phenotypes characteristic of mitochondrial dysfunction, including ataxia and muscular dystrophy. Consistent with this, MSTO1 patient-derived fibroblasts have fragmented mitochondria and a striking loss of mtDNA. Although MSTO1 has been implicated in regulating mitochondrial fusion, the molecular function of this cytosolic protein in vertebrate cells remains unclear. Using the auxin-inducible degradation (AID) system we demonstrate that MSTO1-FLAG-AID protein is rapidly depleted to almost undetectable levels. Importantly, these cells recapitulate the fragmented mitochondrial phenotype observed in patients and thus are a valuable model of disease. Surprisingly, prior to any changes in mitochondria, we show that MSTO1-depleted cells have a significant decrease in TRiC levels, an essential cytosolic ATP-dependent chaperone required to fold diverse substrates, including actin and tubulin. We reveal that TRiC is also reduced in MSTO1 patient-derived fibroblasts, indicating that loss of TRiC may contribute to disease pathophysiology. We further demonstrate that knockdown of TRiC leads to a decrease in MSTO1 protein levels and remarkably, was sufficient to induce a fragmented mitochondrial phenotype, independent of changes in tubulin or actin. This reveals a previously unrecognized connection between TRiC and mitochondrial homeostasis. Using co-immunoprecipitation we found that MSTO1 interacts with the TRiC chaperone. We also observe accumulation of early TRiC assembly subcomplexes in the absence of MSTO1 suggesting that MSTO1 facilitates assembly of TRiC. Together, our findings identify MSTO1 as a TRiC assembly factor and connect mitochondrial defects caused by MSTO1-depletion to the loss of TRiC.
Source: MSTO1 functions as a TRiC assembly factor linking cytosolic proteostasis to mitochondrial function