The assembly of the Mitochondrial Complex I Assembly complex uncovers a redox pathway coordination

McGregor, Lindsay; Acajjaoui, Samira; Desfosses, Ambroise; Saïdi, Melissa; Bacia-Verloop, Maria; Schwarz, Jennifer J.; Juyoux, Pauline; von Velsen, Jill; Bowler, Matthew W.; McCarthy, Andrew A.; Kandiah, Eaazhisai; Gutsche, Irina; Soler-Lopez, Montserrat

doi:10.1038/s41467-023-43865-0

Cited by 4 publications

(4 citation statements)

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“… 30 The catalytic core of complex I, comprises essential NDUF subunits facilitating electron transfer from NADH to ubiquinone, crucial for oxidative phosphorylation and mitochondrial energy production. 31 , 32 Prior research links cardiac hypertrophy pathophysiology to dysfunctional complex I. Mitochondrial dysfunction, particularly involving complex I and II activity, plays a significant role in ventricular hypertrophy, heart failure and cardiac dysfunction. Mitochondrial dysfunction is associated with altered mitochondrial morphology, apoptosis initiation and cardiomyocyte loss, contributing to ventricular decompensation and the development of heart failure.…”

Section: Discussionmentioning

confidence: 99%

HINT2 protects against pressure overload‐induced cardiac remodelling through mitochondrial pathways

Zhang,

Zhou,

Meng

et al. 2024

J Cellular Molecular Medi

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Histidine triad nucleotide‐binding protein 2 (HINT2) is an enzyme found in mitochondria that functions as a nucleotide hydrolase and transferase. Prior studies have demonstrated that HINT2 plays a crucial role in ischemic heart disease, but its importance in cardiac remodelling remains unknown. Therefore, the current study intends to determine the role of HINT2 in cardiac remodelling. HINT2 expression levels were found to be lower in failing hearts and hypertrophy cardiomyocytes. The mice that overexpressed HINT2 exhibited reduced myocyte hypertrophy and cardiac dysfunction in response to stress. In contrast, the deficiency of HINT2 in the heart of mice resulted in a worsening hypertrophic phenotype. Further analysis indicated that upregulated genes were predominantly associated with the oxidative phosphorylation and mitochondrial complex I pathways in HINT2‐overexpressed mice after aortic banding (AB) treatment. This suggests that HINT2 increases the expression of NADH dehydrogenase (ubiquinone) flavoprotein (NDUF) genes. In cellular studies, rotenone was used to disrupt mitochondrial complex I, and the protective effect of HINT2 overexpression was nullified. Lastly, we predicted that thyroid hormone receptor beta might regulate HINT2 transcriptional activity. To conclusion, the current study showcased that HINT2 alleviates pressure overload‐induced cardiac remodelling by influencing the activity and assembly of mitochondrial complex I. Thus, targeting HINT2 could be a novel therapeutic strategy for reducing cardiac remodelling.

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Section: Discussionmentioning

confidence: 99%

HINT2 protects against pressure overload‐induced cardiac remodelling through mitochondrial pathways

Zhang,

Zhou,

Meng

et al. 2024

J Cellular Molecular Medi

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“…However, recent studies have reached different conclusions. When AβOs accumulate, dephosphorylation of the evolutionarily conserved signaling intermediate of the mitochondrial assembly factor complex core protein in the Toll pathway becomes more pronounced, suggesting excessive assembly of Complex I that results in ROS overproduction and ultimately in damage to the respiratory chain (Mcgregor et al, 2023 ).…”

Section: The Damage Caused By Aβos To Mitochondriamentioning

confidence: 99%

Neurotoxic β-amyloid oligomers cause mitochondrial dysfunction—the trigger for PANoptosis in neurons

Meng,

Song,

Liu

et al. 2024

Front. Aging Neurosci.

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As the global population ages, the incidence of elderly patients with dementia, represented by Alzheimer's disease (AD), will continue to increase. Previous studies have suggested that β-amyloid protein (Aβ) deposition is a key factor leading to AD. However, the clinical efficacy of treating AD with anti-Aβ protein antibodies is not satisfactory, suggesting that Aβ amyloidosis may be a pathological change rather than a key factor leading to AD. Identification of the causes of AD and development of corresponding prevention and treatment strategies is an important goal of current research. Following the discovery of soluble oligomeric forms of Aβ (AβO) in 1998, scientists began to focus on the neurotoxicity of AβOs. As an endogenous neurotoxin, the active growth of AβOs can lead to neuronal death, which is believed to occur before plaque formation, suggesting that AβOs are the key factors leading to AD. PANoptosis, a newly proposed concept of cell death that includes known modes of pyroptosis, apoptosis, and necroptosis, is a form of cell death regulated by the PANoptosome complex. Neuronal survival depends on proper mitochondrial function. Under conditions of AβO interference, mitochondrial dysfunction occurs, releasing lethal contents as potential upstream effectors of the PANoptosome. Considering the critical role of neurons in cognitive function and the development of AD as well as the regulatory role of mitochondrial function in neuronal survival, investigation of the potential mechanisms leading to neuronal PANoptosis is crucial. This review describes the disruption of neuronal mitochondrial function by AβOs and elucidates how AβOs may activate neuronal PANoptosis by causing mitochondrial dysfunction during the development of AD, providing guidance for the development of targeted neuronal treatment strategies.

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“…Upon TLR4 activation, the TLR4 adapter protein TRAF6 (TNF receptor-associated factor 6) translocates to the mitochondria and interacts with ECSIT (Evolutionarily conserved signaling intermediate in Toll pathway, mitochondrial), promoting its ubiquitination. ECSIT, a subunit of the Mitochondrial respiratory chain Complex I Assembly complex (MCIA), is thought to be one of the chaperones for complex I [31][32][33]. When ECSIT is ubiquitinated, MCIA undergoes degradation, leading to the increased production of reactive oxygen species (ROS) in mitochondria [34].…”

Section: The Mechanism Of Gga-induced Cell Deathmentioning

confidence: 99%

Inhibition of Hepatocellular Carcinoma by Endogenous Lipids: Induction of Pyroptosis by Geranylgeranoic Acid—A Comparison with Palmitic Acid and Retinoic Acid

Shidoji

2024

Preprint

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Research on retinoid-based cancer prevention, spurred by the effects of vitamin A deficiency on gastric cancer and subsequent clinical studies on digestive tract cancer, unveils novel avenues for chemoprevention. Acyclic retinoids like 4,5-didehydrogeranylgeranoic acid (4,5-didehydroGGA) emerged as potent agents against hepatocellular carcinoma (HCC), distinct from natural retinoids such as all-trans retinoic acid (ATRA). Mechanistic studies reveal GGA's unique induction of pyroptosis, a rapid cell death pathway, in HCC cells. GGA triggers mitochondrial superoxide hyperproduction and ER stress responses through Toll-like receptor 4 (TLR4) signaling and modulates autophagy, ultimately activating pyroptotic cell death in HCC cells. Unlike ATRA-induced apoptosis, GGA and palmitic acid (PA) induce pyroptosis, underscoring their distinct mechanisms. While all three fatty acids evoke mitochondrial dysfunction and ER stress responses, GGA and PA inhibit autophagy, leading to incomplete autophagic responses and pyroptosis, whereas ATRA promotes autophagic flux. In vivo experiments demonstrate GGA's potential as an anti-oncometabolite, inducing cell death selectively in tumor cells and thus suppressing liver cancer development. This review provides a comprehensive overview of the molecular mechanisms underlying GGA's anti-HCC effects and underscores its promising role in cancer prevention, highlighting its importance in HCC prevention.

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The assembly of the Mitochondrial Complex I Assembly complex uncovers a redox pathway coordination

Cited by 4 publications

References 50 publications

HINT2 protects against pressure overload‐induced cardiac remodelling through mitochondrial pathways

HINT2 protects against pressure overload‐induced cardiac remodelling through mitochondrial pathways

Neurotoxic β-amyloid oligomers cause mitochondrial dysfunction—the trigger for PANoptosis in neurons

Inhibition of Hepatocellular Carcinoma by Endogenous Lipids: Induction of Pyroptosis by Geranylgeranoic Acid—A Comparison with Palmitic Acid and Retinoic Acid

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