Mutations in TOMM70 lead to multi-OXPHOS deficiencies and cause severe anemia, lactic acidosis, and developmental delay

Wei, Xiujuan; Du, Miaomiao; Xie, Jun; Luo, Ting; Zhou, Yan; Zhang, Kun; Li, Jin; Chen, Deyu; Xu, Pu; Jia, Manli; Zhou, Huaibin; Fang, Hezhi; Lyu, Jianxin; Yang, Yanling

doi:10.1038/s10038-019-0714-1

Cited by 25 publications

(31 citation statements)

References 30 publications

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“…Homozygous null drosophila models of patient mutations resulted in pupae lethality, indicating that the mutations are loss of function alleles [82]. A further patient identified with a compound heterozygous mutation (T265M and A582V) presented with severe anaemia, lactic acidosis and developmental delay ( Table 1) [83]. The T265M mutation is not in a known Tom70 domain, where the A582V mutation is in a TPR domain, potentially affecting substrate binding of Tom70 [83,84].…”

Section: Mitochondrial Disease and The Tom Complexmentioning

confidence: 99%

“…A further patient identified with a compound heterozygous mutation (T265M and A582V) presented with severe anaemia, lactic acidosis and developmental delay ( Table 1) [83]. The T265M mutation is not in a known Tom70 domain, where the A582V mutation is in a TPR domain, potentially affecting substrate binding of Tom70 [83,84]. Patient cells had reduced levels of the Tom70 dimer, and Tom70 was not detected in the TOM complex by Blue Native PAGE [83].…”

Section: Mitochondrial Disease and The Tom Complexmentioning

confidence: 99%

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Mitochondrial protein import dysfunction: mitochondrial disease, neurodegenerative disease and cancer

2021

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The majority of proteins localised to mitochondria are encoded by the nuclear genome, with approximately 1500 proteins imported into mammalian mitochondria. Dysfunction in this fundamental cellular process is linked to a variety of pathologies including neuropathies, cardiovascular disorders, myopathies, neurodegenerative diseases and cancer, demonstrating the importance of mitochondrial protein import machinery for cellular function. Correct import of proteins into mitochondria requires the co‐ordinated activity of multimeric protein translocation and sorting machineries located in both the outer and inner mitochondrial membranes, directing the imported proteins to the destined mitochondrial compartment. This dynamic process maintains cellular homeostasis, and its dysregulation significantly affects cellular signalling pathways and metabolism. This review summarises current knowledge of the mammalian mitochondrial import machinery and the pathological consequences of mutation of its components. In addition, we will discuss the role of mitochondrial import in cancer, and our current understanding of the role of mitochondrial import in neurodegenerative diseases including Alzheimer's disease, Huntington's disease and Parkinson's disease.

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Section: Mitochondrial Disease and The Tom Complexmentioning

confidence: 99%

Section: Mitochondrial Disease and The Tom Complexmentioning

confidence: 99%

Mitochondrial protein import dysfunction: mitochondrial disease, neurodegenerative disease and cancer

2021

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“…The recently discovered roles of TOM70 in many pathological contexts suggest that also mutations in the TOMM70 gene could be involved in the development of such mitochondriopathies in humans. Indeed, two recent studies reported on mutations in TOMM70 that caused neurological impairment, developmental delay, severe anemia, and lactic acidosis [ 172 , 220 ]. The clinical consequences of these mutations indicate that essential mitochondrial functions were substantially impaired.…”

Section: Tom70 In Health and Diseasementioning

confidence: 99%

The Mitochondrial Outer Membrane Protein Tom70-Mediator in Protein Traffic, Membrane Contact Sites and Innate Immunity

Kreimendahl

Rassow

2020

IJMS

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Tom70 is a versatile adaptor protein of 70 kDa anchored in the outer membrane of mitochondria in metazoa, fungi and amoeba. The tertiary structure was resolved for the Tom70 of yeast, showing 26 α-helices, most of them participating in the formation of 11 tetratricopeptide repeat (TPR) motifs. Tom70 serves as a docking site for cytosolic chaperone proteins and co-chaperones and is thereby involved in the uptake of newly synthesized chaperone-bound proteins in mitochondrial biogenesis. In yeast, Tom70 additionally mediates ER-mitochondria contacts via binding to sterol transporter Lam6/Ltc1. In mammalian cells, TOM70 promotes endoplasmic reticulum (ER) to mitochondria Ca2+ transfer by association with the inositol-1,4,5-triphosphate receptor type 3 (IP3R3). TOM70 is specifically targeted by the Bcl-2-related protein MCL-1 that acts as an anti-apoptotic protein in macrophages infected by intracellular pathogens, but also in many cancer cells. By participating in the recruitment of PINK1 and the E3 ubiquitin ligase Parkin, TOM70 can be implicated in the development of Parkinson’s disease. TOM70 acts as receptor of the mitochondrial antiviral-signaling protein (MAVS) and thereby participates in the corresponding system of innate immunity against viral infections. The protein encoded by Orf9b in the genome of SARS-CoV-2 binds to TOM70, probably compromising the synthesis of type I interferons.

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“…13 In particular, patients with abnormal TOM70 function suffer from lactic acidosis. 16 By interacting with TOM70, Orf9b may induce the production of lactic acid, which has been proven to inhibit IFN-I responses. 17 Considering the critical role of IFN-I in the human antiviral response, restoration of IFN-I production in COVID-19 patients may prove to be a significantly effective therapeutic option.…”

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confidence: 99%

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SARS-CoV-2 Orf9b suppresses type I interferon responses by targeting TOM70

et al. 2020

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Mutations in TOMM70 lead to multi-OXPHOS deficiencies and cause severe anemia, lactic acidosis, and developmental delay

Cited by 25 publications

References 30 publications

Mitochondrial protein import dysfunction: mitochondrial disease, neurodegenerative disease and cancer

Mitochondrial protein import dysfunction: mitochondrial disease, neurodegenerative disease and cancer

The Mitochondrial Outer Membrane Protein Tom70-Mediator in Protein Traffic, Membrane Contact Sites and Innate Immunity

SARS-CoV-2 Orf9b suppresses type I interferon responses by targeting TOM70

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