Hotspots for Disease-Causing Mutations in the Mitochondrial TIM23 Import Complex

Sahil Jain*, Eyal Paz, Abdussalam Azem

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

Abstract

The human mitochondrial proteome comprises approximately 1500 proteins, with only 13 being encoded by mitochondrial DNA. The remainder are encoded by the nuclear genome, translated by cytosolic ribosomes, and subsequently imported into and sorted within mitochondria. The process of mitochondria-destined protein import is mediated by several intricate protein complexes distributed among the four mitochondrial compartments. The focus of this mini-review is the translocase of the inner membrane 23 (TIM23) complex that assists in the import of ~60% of the mitochondrial proteome, which includes the majority of matrix proteins as well as some inner membrane and intermembrane space proteins. To date, numerous pathogenic mutations have been reported in the genes encoding various components of the TIM23 complex. These diseases exhibit mostly developmental and neurological defects at an early age. Interestingly, accumulating evidence supports the possibility that the gene for Tim50 represents a hotspot for disease-causing mutations among core TIM23 complex components, while genes for the mitochondrial Hsp70 protein (mortalin) and its J domain regulators represent hotspots for mutations affecting presequence translocase-associated motor (PAM) subunits. The potential mechanistic implications of the discovery of disease-causing mutations on the function of the TIM23 complex, in particular Tim50, are discussed.

Original languageEnglish
Article number1534
JournalGenes
Volume15
Issue number12
DOIs
StatePublished - Dec 2024

Funding

FundersFunder number
Israel Science Foundation

    Keywords

    • TIM23 complex
    • Timm50
    • mitochondrial protein import
    • rare genetic disorders

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