AIF meets the CHCHD4/Mia40-dependent mitochondrial import pathway

Reinhardt, Camille; Arena, Giuseppe; Nedara, Kenza; Edwards, Ruairidh; Brenner, Catherine; Tokatlidis, Kostas; Modjtahedi, Nazanine

doi:10.1016/j.bbadis.2020.165746

Cited by 38 publications

(40 citation statements)

References 181 publications

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“…The molecular disease-causing mechanism of AIFM1 mutation-related hearing loss is still unclear; the mitochondrial function and the caspase-independent apoptosis to neuronal development and adult neurogenesis play a critical role in previous studies [ 47 , 48 ]. In our recent study, we found that the AIFM1 mutation led to decreased dimerization and further impaired mitochondrial functions, such as increase of ROS production and impairment of mitochondrial membrane potential, thereby activating caspase-independent apoptosis (unpublished data).…”

Section: Discussionmentioning

confidence: 99%

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High Frequency of AIFM1 Variants and Phenotype Progression of Auditory Neuropathy in a Chinese Population

Wang

Dai

et al. 2020

Neural Plasticity

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To decipher the genotype-phenotype correlation of auditory neuropathy (AN) caused by AIFM1 variations, as well as the phenotype progression of these patients, exploring the potential molecular pathogenic mechanism of AN. A total of 36 families of individuals with AN (50 cases) with AIFM1 variations were recruited and identified by Sanger sequencing or next-generation sequencing; the participants included 30 patients from 16 reported families and 20 new cases. We found that AIFM1-positive cases accounted for 18.6% of late-onset AN cases. Of the 50 AN patients with AIFM1 variants, 45 were male and 5 were female. The hotspot variation of this gene was p.Leu344Phe, accounting for 36.1%. A total of 19 AIFM1 variants were reported in this study, including 7 novel ones. A follow-up study was performed on 30 previously reported AIFM1-positive subjects, 16 follow-up cases (53.3%) were included in this study, and follow-up periods were recorded from 1 to 23 years with average 9.75±9.89 years. There was no hearing threshold increase during the short-term follow-up period (1-10 years), but the low-frequency and high-frequency hearing thresholds showed a significant increase with the prolongation of follow-up time. The speech discrimination score progressed gradually and significantly along with the course of the disease and showed a more serious decline, which was disproportionately worse than the pure tone threshold. In addition to the X-linked recessive inheritance pattern, the X-linked dominant inheritance pattern is also observed in AIFM1-related AN and affects females. In conclusion, we confirmed that AIFM1 is the primary related gene among late-onset AN cases, and the most common recurrent variant is p.Leu344Phe. Except for the X-linked recessive inheritance pattern, the X-linked dominant inheritance pattern is another probability of AIFM1-related AN, with females affected. Phenotypical features of AIFM1-related AN suggested that auditory dyssynchrony progressively worsened over time.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 82%

High Frequency of AIFM1 Variants and Phenotype Progression of Auditory Neuropathy in a Chinese Population

Wang

Dai

et al. 2020

Neural Plasticity

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“…S1F). One of these proteins, CHCHD4, has been previously reported to directly interact with full-length AIFM1 (Hangen et al, 2015;Reinhardt et al, 2020).…”

Section: Definition Of the Mitochondrial Matrix And Ims Bioid Environmentioning

confidence: 99%

A high-density human mitochondrial proximity interaction network

Antonická

Lin

Janer

et al. 2020

Preprint

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We used BioID, a proximity-dependent biotinylation assay, to interrogate 100 mitochondrial baits from all mitochondrial sub-compartments to create a high resolution human mitochondrial proximity interaction network. We identified 1465 proteins, producing 15626 unique high confidence proximity interactions. Of these, 528 proteins were previously annotated as mitochondrial, nearly half of the mitochondrial proteome defined by Mitocarta 2.0. Bait-bait analysis showed a clear separation of mitochondrial compartments, and correlation analysis among preys across all baits allowed us to identify functional clusters involved in diverse mitochondrial functions, and to assign uncharacterized proteins to specific modules. We demonstrate that this analysis can assign isoforms of the same mitochondrial protein to different mitochondrial sub-compartments, and show that some proteins may have multiple cellular locations. Outer membrane baits showed specific proximity interactions with cytosolic proteins and proteins in other organellar membranes, suggesting specialization of proteins responsible for contact site formation between mitochondria and individual organelles. This proximity network will be a valuable resource for exploring the biology of uncharacterized mitochondrial proteins, the interactions of mitochondria with other cellular organelles, and will provide a framework to interpret alterations in sub-mitochondrial environments associated with mitochondrial disease. Bullet points• We created a high resolution human mitochondrial protein proximity map using BioID• Bait-bait analysis showed that the map has sub-compartment resolution and correlation analysis of preys identified functional clusters and assigned proteins to specific modules• We identified isoforms of matrix and IMS proteins with multiple cellular localizations and an endonuclease that localizes to both the matrix and the OMM • OMM baits showed specific interactions with non-mitochondrial proteins reflecting organellar contact sites and protein dual localization 2013). Mitochondrial diseases due to deficiencies in the oxidative phosphorylation machinery are amongst the most common inherited metabolic disorders (Frazier et al., 2019;Nunnari and Suomalainen, 2012). While nearly 300 causal genes have now been identified, the molecular basis for the extraordinary tissue specificity associated with these diseases remains an enduring mystery.Mitochondria are double-membraned organelles, whose ultrastructure has been investigated for decades. The outer membrane (OMM), which serves as a platform for molecules involved in the regulation of innate immunity and for regulation of apoptosis, is permeable to metabolites and small proteins, and it forms close contacts with the endoplasmic reticulum (ER) for the exchange of lipids and calcium (Csordas et al., 2018). The impermeable inner membrane (IMM) is composed of invaginations called cristae that contain the complexes of the oxidative phosphorylation system. The intermembrane space (IMS) comprises both the space formed...

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“…While the working components of the DRS were first described in yeast [ 5 , 6 , 8 , 13 , 14 , 31 ], they have been subsequently shown to be functionally conserved in higher organisms [ 4 , 11 , 17 , 18 , 27 , 51–53 , 59 ]. This functional conservation is underscored by the fact that the key components of the DRS are essential across species: loss of Chchd4 has been shown to be lethal in mice [ 17 ] and zebrafish [ 18 ], as it was shown in yeast [ 5 , 8 ].…”

Section: The Drs Is Evolutionarily Conservedmentioning

confidence: 99%

CHCHD4 (MIA40) and the mitochondrial disulfide relay system

Al-Habib

Ashcroft

2021

Biochemical Society Transactions

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Mitochondria are pivotal for normal cellular physiology, as they perform a crucial role in diverse cellular functions and processes, including respiration and the regulation of bioenergetic and biosynthetic pathways, as well as regulating cellular signalling and transcriptional networks. In this way, mitochondria are central to the cell's homeostatic machinery, and as such mitochondrial dysfunction underlies the pathology of a diverse range of diseases including mitochondrial disease and cancer. Mitochondrial import pathways and targeting mechanisms provide the means to transport into mitochondria the hundreds of nuclear-encoded mitochondrial proteins that are critical for the organelle's many functions. One such import pathway is the highly evolutionarily conserved disulfide relay system (DRS) within the mitochondrial intermembrane space (IMS), whereby proteins undergo a form of oxidation-dependent protein import. A central component of the DRS is the oxidoreductase coiled-coil-helix-coiled-coil-helix (CHCH) domain-containing protein 4 (CHCHD4, also known as MIA40), the human homologue of yeast Mia40. Here, we summarise the recent advances made to our understanding of the role of CHCHD4 and the DRS in physiology and disease, with a specific focus on the emerging importance of CHCHD4 in regulating the cellular response to low oxygen (hypoxia) and metabolism in cancer.

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AIF meets the CHCHD4/Mia40-dependent mitochondrial import pathway

Cited by 38 publications

References 181 publications

High Frequency of AIFM1 Variants and Phenotype Progression of Auditory Neuropathy in a Chinese Population

High Frequency of AIFM1 Variants and Phenotype Progression of Auditory Neuropathy in a Chinese Population

A high-density human mitochondrial proximity interaction network

CHCHD4 (MIA40) and the mitochondrial disulfide relay system

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