Mutant CHCHD10 causes an extensive metabolic rewiring that precedes OXPHOS dysfunction in a murine model of mitochondrial cardiomyopathy

Sayles, Nicole M.; Southwell, Nneka; McAvoy, Kevin; Kim, Kihwan; Pesini, Alba; Anderson, Corey; Quinzii, Catarina M.; Cloonan, Suzanne M.; Kawamata, Hibiki; Manfredi, Giovanni

doi:10.1016/j.celrep.2022.110475

Cited by 16 publications

(56 citation statements)

References 79 publications

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“…Since no defect in mitochondrial respiratory chain complex assembly was observed in the double chchd10 -/- & chchd2 -/- model, we investigated whether other mechanisms could be underlying the observed deficits. As the mt-ISR has been documented in CHCHD10/2 models (18–20, 22), we explored whether the RNA levels of ISR markers were increased in the KO models at 5 dpf. While this pathway was not activated in the single gene KO models, a number of markers were increased in the double chchd10 -/- & chchd2 -/- model compared to wild type larvae.…”

Section: Resultsmentioning

confidence: 99%

“…This suggests that reduced assembly of Complex I may not be solely responsible for the ALS-like phenotypes, but that other, more deleterious, cellular pathways are altered. The mt-ISR, a conserved transcriptional response that can be a triggered by mitochondrial dysfunction (56), has been linked to neurodegeneration (57) and has been described in CHCHD10/2 models previously (18–22). Transcripts for all three upstream mt-ISR activators ( atf4, atf5, chop ) (56), and fgf21 , a biomarker of mitochondrial stress (58, 59) were significantly increased in our double chchd10 -/- & chchd2 -/- model, but not in the single KO models.…”

Section: Discussionmentioning

confidence: 99%

“…This is in line with previous studies where activation of the mt-ISR was observed in both CHCHD10 S55L knock-in mice (19), double KO mice and cells (20, 21), but not in CHCHD10 KO mice. A recent study using CHCHD10 S55L mice suggested that mt-ISR precedes OXPHOS deficiency due to CHCHD10 protein aggregation (22). In contrast, our single gene KO models results suggest that OXPHOS deficiency is independent of the mt-ISR.…”

Section: Discussionmentioning

confidence: 99%

“…CHCHD2 and CHCHD10 share 58% sequence identity and have a common ancestor in yeast, suggesting that these proteins might have partially overlapping function (15). In vitro studies have reported that loss of either CHCHD2, CHCHD10 or both, impacts mitochondrial respiration (10, 16), survival/growth following exposure to various cellular stressors (9, 10, 16, 17), the mitochondrial integrated stress response (mt-ISR) (18–22), apoptosis (23, 24), as well as the transcription of the oxygen responsive gene COX4I2 (25–27).…”

Section: Introductionmentioning

confidence: 99%

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Loss of mitochondrial Chchd10 or Chchd2 in zebrafish leads to an ALS-like phenotype and Complex I deficiency independent of the mt-ISR

Légaré¹,

Rampal²,

Aaltonen

et al. 2022

Preprint

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Mutations in CHCHD10 and CHCHD2, coding for two paralogous mitochondrial proteins, have been identified in amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTD), and Parkinson's disease (PD). Here we investigated the biological roles of these proteins during vertebrate development using knockout (KO) models in zebrafish. We demonstrate that loss of either or both proteins leads to a motor impairment, reduced survival, and compromised neuromuscular junction (NMJ) integrity in larval zebrafish. Compensation by Chchd10 was observed in the chchd2-/- model, but not by Chchd2 in the chchd10 -/- model. The assembly of mitochondrial respiratory chain Complex I was impaired in chchd10 -/- and chchd2 -/- zebrafish larvae, but unexpectedly not in the double chchd10 -/- & chchd2 -/- model, suggesting that reduced mitochondrial Complex I cannot be solely responsible for the observed phenotypes, which are generally more severe in the double KO. Activation of the mitochondrial integrated stress response (mt-ISR) was only observed in the double KO model, possibly implicating this pathway in the recovery of the Complex I defect, and suggesting that Complex I assembly defect in our single KO is independent of the mt-ISR. Our results demonstrate that both proteins are required for normal vertebrate development, but their precise molecular function in the mitochondrial biology of motor neurons remains to be discovered.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Loss of mitochondrial Chchd10 or Chchd2 in zebrafish leads to an ALS-like phenotype and Complex I deficiency independent of the mt-ISR

Légaré¹,

Rampal²,

Aaltonen

et al. 2022

Preprint

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“…A multi-omics study, in which transcriptomics, metabolomics, proteomics, and molecular and biochemical analyses were performed using the CHCHD10 S59L knock-in mouse heart, revealed that mtISR is associated with CHCHD2 and CHCHD10 aggregation and leads to metabolic rearrangement, including the activation of serine biosynthesis and one-carbon metabolism (Sayles et al, 2022). OXPHOS deficiency was preceded by mtISR and metabolic reprogramming (Sayles et al, 2022).…”

Section: Dysfunction Of Chchd2 and Chchdinduces Mtisrmentioning

confidence: 99%

Neurodegeneration-associated mitochondrial proteins, CHCHD2 and CHCHD10–what distinguishes the two?

Ikeda

Imai

2022

Front. Cell Dev. Biol.

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Coiled-coil-helix-coiled-coil-helix domain containing 2 (CHCHD2) and Coiled-coil-helix-coiled-coil-helix domain containing 10 (CHCHD10) are mitochondrial proteins that are thought to be genes which duplicated during evolution and are the causative genes for Parkinson’s disease and amyotrophic lateral sclerosis/frontotemporal lobe dementia, respectively. CHCHD2 forms a heterodimer with CHCHD10 and a homodimer with itself, both of which work together within the mitochondria. Various pathogenic and disease-risk variants have been identified; however, how these mutations cause neurodegeneration in specific diseases remains a mystery. This review focuses on important new findings published since 2019 and discusses avenues to solve this mystery.

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Loss of mitochondrial Chchd10 or Chchd2 in zebrafish leads to an ALS‐like phenotype and Complex I deficiency independent of the mitochondrial integrated stress response

Légaré

Rampal

Gurberg

et al. 2023

Developmental Neurobiology

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Mutations in CHCHD10 and CHCHD2, encoding two paralogous mitochondrial proteins, have been identified in cases of amyotrophic lateral sclerosis, frontotemporal lobar degeneration, and Parkinson's disease. Their role in disease is unclear, though both have been linked to mitochondrial respiration and mitochondrial stress responses. Here, we investigated the biological roles of these proteins during vertebrate development using knockout (KO) models in zebrafish. We demonstrate that loss of either or both proteins leads to motor impairment, reduced survival and compromised neuromuscular junction integrity in larval zebrafish. Compensation by Chchd10 was observed in the chchd2−/− model, but not by Chchd2 in the chchd10−/− model. The assembly of mitochondrial respiratory chain Complex I was impaired in chchd10−/− and chchd2−/− zebrafish larvae, but unexpectedly not in a double chchd10−/− and chchd2−/− model, suggesting that reduced mitochondrial Complex I cannot be solely responsible for the observed phenotypes, which are generally more severe in the double KO. We observed transcriptional activation markers of the mitochondrial integrated stress response (mt‐ISR) in the double chchd10−/− and chchd2−/− KO model, suggesting that this pathway is involved in the restoration of Complex I assembly in our double KO model. The data presented here demonstrates that the Complex I assembly defect in our single KO models arises independently of the mt‐ISR. Furthermore, this study provides evidence that both proteins are required for normal vertebrate development.

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Mutant CHCHD10 causes an extensive metabolic rewiring that precedes OXPHOS dysfunction in a murine model of mitochondrial cardiomyopathy

Cited by 16 publications

References 79 publications

Loss of mitochondrial Chchd10 or Chchd2 in zebrafish leads to an ALS-like phenotype and Complex I deficiency independent of the mt-ISR

Loss of mitochondrial Chchd10 or Chchd2 in zebrafish leads to an ALS-like phenotype and Complex I deficiency independent of the mt-ISR

Neurodegeneration-associated mitochondrial proteins, CHCHD2 and CHCHD10–what distinguishes the two?

Loss of mitochondrial Chchd10 or Chchd2 in zebrafish leads to an ALS‐like phenotype and Complex I deficiency independent of the mitochondrial integrated stress response

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