Loss of CHCHD2 Stability Coordinates with C1QBP/CHCHD2/CHCHD10 Complex Impairment to Mediate PD-Linked Mitochondrial Dysfunction

Ren, Yan-Lin; Jiang, Zheng; Wang, Jia-Yi; He, Qin; Li, Si-Xu; Gu, Xiao-Jing; Qi, Yang-Ran; Zhang, Min; Yang, Wen-Jie; Cao, Bei; Li, Jing-Yu; Wang, Yi; Chen, Yong-Ping

doi:10.1007/s12035-024-04090-y

Cited by 3 publications

References 74 publications

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The CHCHD2-CHCHD10 protein complex is modulated by mitochondrial dysfunction and alters lipid homeostasis in the mouse brain

Gerlach,

Pireddu,

Zhang

et al. 2024

Preprint

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The highly conserved CHCHD2 and CHCHD10 are small mitochondrial proteins residing in the intermembrane space. Recently, mutations in theCHCHD2andCHCHD10genes have been linked to severe disorders, including Parkinson’s disease and amyotrophic lateral sclerosis. In cultured cells, a small fraction of CHCHD2 and CHCHD10 oligomerize to form a high molecular weight complex of unknown function. Here, we generated a whole-bodyChchd2knockout mouse to investigate thein vivorole of CHCHD2 and its protein complex. We show that CHCHD2 is crucial for sustaining full motor capacity, normal striatal dopamine levels, and lipid homeostasis in the brain of adult male mice. We also demonstrate that in mouse tissues, CHCHD2 and CHCHD10 exist exclusively as a high molecular weight complex, whose levels are finely tuned under physiological conditions. In response to mitochondrial dysfunction, the abundance and size of the CHCHD2-CHCHD10 complex increases, a mechanism conserved across different tissues. Although the loss of CHCHD2 does not abolish CHCHD10 oligomerization, it enhances cell vulnerability to mitochondrial stress, suggesting that CHCHD2 is protective against mitochondrial damage. Our findings uncover the role of CHCHD2 in preserving tissue homeostasis and provide important insights into the involvement of the CHCHD2-CHCHD10 complex in human diseases.

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The CHCHD2-CHCHD10 protein complex is modulated by mitochondrial dysfunction and alters lipid homeostasis in the mouse brain

Gerlach,

Pireddu,

Zhang

et al. 2024

Preprint

View full text Add to dashboard Cite

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DNA Damage and Parkinson’s Disease

Pfeifer

2024

IJMS

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The etiology underlying most sporadic Parkinson’s’ disease (PD) cases is unknown. Environmental exposures have been suggested as putative causes of the disease. In cell models and in animal studies, certain chemicals can destroy dopaminergic neurons. However, the mechanisms of how these chemicals cause the death of neurons is not understood. Several of these agents are mitochondrial toxins that inhibit the mitochondrial complex I of the electron transport chain. Familial PD genes also encode proteins with important functions in mitochondria. Mitochondrial dysfunction of the respiratory chain, in combination with the presence of redox active dopamine molecules in these cells, will lead to the accumulation of reactive oxygen species (ROS) in dopaminergic neurons. Here, I propose a mechanism regarding how ROS may lead to cell killing with a specificity for neurons. One rarely considered hypothesis is that ROS produced by defective mitochondria will lead to the formation of oxidative DNA damage in nuclear DNA. Many genes that encode proteins with neuron-specific functions are extraordinary long, ranging in size from several hundred kilobases to well over a megabase. It is predictable that such long genes will contain large numbers of damaged DNA bases, for example in the form of 8-oxoguanine (8-oxoG), which is a major DNA damage type produced by ROS. These DNA lesions will slow down or stall the progression of RNA polymerase II, which is a term referred to as transcription stress. Furthermore, ROS-induced DNA damage may cause mutations, even in postmitotic cells such as neurons. I propose that the impaired transcription and mutagenesis of long, neuron-specific genes will lead to a loss of neuronal integrity, eventually leading to the death of these cells during a human lifetime.

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Targeting Mitochondrial Dysfunction and Reactive Oxygen Species for Neurodegenerative Disease Treatment

Choi,

Kim,

Park

2024

IJMS

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Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the most common neurodegenerative diseases, and they affect millions of people worldwide, particularly older individuals. Therefore, there is a clear need to develop novel drug targets for the treatment of age-related neurodegenerative diseases. Emerging evidence suggests that mitochondrial dysfunction and reactive oxygen species (ROS) generation play central roles in the onset and progression of neurodegenerative diseases. Mitochondria are key regulators of respiratory function, cellular energy adenosine triphosphate production, and the maintenance of cellular redox homeostasis, which are essential for cell survival. Mitochondrial morphology and function are tightly regulated by maintaining a balance among mitochondrial fission, fusion, biogenesis, and mitophagy. In this review, we provide an overview of the main functions of mitochondria, with a focus on recent progress highlighting the critical role of ROS−induced oxidative stress, dysregulated mitochondrial dynamics, mitochondrial apoptosis, mitochondria-associated inflammation, and impaired mitochondrial function in the pathogenesis of age-related neurodegenerative diseases, such as AD and PD. We also discuss the potential of mitochondrial fusion and biogenesis enhancers, mitochondrial fission inhibitors, and mitochondria-targeted antioxidants as novel drugs for the treatment of these diseases.

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Loss of CHCHD2 Stability Coordinates with C1QBP/CHCHD2/CHCHD10 Complex Impairment to Mediate PD-Linked Mitochondrial Dysfunction

Cited by 3 publications

References 74 publications

The CHCHD2-CHCHD10 protein complex is modulated by mitochondrial dysfunction and alters lipid homeostasis in the mouse brain

The CHCHD2-CHCHD10 protein complex is modulated by mitochondrial dysfunction and alters lipid homeostasis in the mouse brain

DNA Damage and Parkinson’s Disease

Targeting Mitochondrial Dysfunction and Reactive Oxygen Species for Neurodegenerative Disease Treatment

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