Abstract
The assembly pathways of mitochondrial respirasome (supercomplex I+III2+IV) are not fully understood. Here, we show that an early sub-complex I assembly, rather than holo-complex I, is sufficient to initiate mitochondrial respirasome assembly. We find that a distal part of the membrane arm of complex I (PD-a module) is a scaffold for the incorporation of complexes III and IV to form a respirasome subcomplex. Depletion of PD-a, rather than other complex I modules, decreases the steady-state levels of complexes III and IV. Both HEK293T cells lacking TIMMDC1 and patient-derived cells with disease-causing mutations in TIMMDC1 showed accumulation of this respirasome subcomplex. This suggests that TIMMDC1, previously known as a complex-I assembly factor, may function as a respirasome assembly factor. Collectively, we provide a detailed, cooperative assembly model in which most complex-I subunits are added to the respirasome subcomplex in the lateral stages of respirasome assembly.
Keywords:
Leigh syndrome; TIMMDC1; cooperative assembly; mitochondrial respirasome; oxidative phosphorylation.
Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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B-Lymphocytes
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Cell Line, Transformed
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Developmental Disabilities / genetics
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Developmental Disabilities / metabolism
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Developmental Disabilities / pathology
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Electron Transport Complex I / antagonists & inhibitors
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Electron Transport Complex I / genetics*
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Electron Transport Complex I / metabolism
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Electron Transport Complex III / antagonists & inhibitors
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Electron Transport Complex III / genetics*
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Electron Transport Complex III / metabolism
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Electron Transport Complex IV / antagonists & inhibitors
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Electron Transport Complex IV / genetics*
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Electron Transport Complex IV / metabolism
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Embryo, Nonmammalian
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Gene Expression Regulation, Developmental
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HEK293 Cells
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Humans
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Mitochondria / genetics*
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Mitochondria / metabolism
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Mitochondrial Membranes / metabolism
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Mitochondrial Precursor Protein Import Complex Proteins / deficiency
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Mitochondrial Precursor Protein Import Complex Proteins / genetics*
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Morpholinos / genetics
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Morpholinos / metabolism
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Muscle Hypotonia / genetics
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Muscle Hypotonia / metabolism
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Muscle Hypotonia / pathology
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Oxidative Phosphorylation
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Zebrafish
Substances
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Mitochondrial Precursor Protein Import Complex Proteins
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Morpholinos
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TIMMDC1 protein, human
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Electron Transport Complex IV
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Electron Transport Complex I
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Electron Transport Complex III