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Mitochondrial dysfunction-induced H3K27 hyperacetylation perturbs enhancers in Parkinson's disease.

ABSTRACT: Mitochondrial dysfunction is a major pathophysiological contributor to the progression of Parkinson's disease (PD); however, whether it contributes to epigenetic dysregulation remains unknown. Here, we show that both chemically and genetically driven mitochondrial dysfunctions share a common mechanism of epigenetic dysregulation. Under both scenarios, lysine 27 acetylation of likely variant H3.3 (H3.3K27ac) increased in dopaminergic neuronal models of PD, thereby opening that region to active enhancer activity via H3K27ac. These vulnerable epigenomic loci represent potential transcription factor motifs for PD pathogenesis. We further confirmed that mitochondrial dysfunction induces H3K27ac in ex vivo and in vivo (MitoPark) neurodegenerative models of PD. Notably, the significantly increased H3K27ac in postmortem PD brains highlights the clinical relevance to the human PD population. Our results reveal an exciting mitochondrial dysfunction-metabolism-H3K27ac-transcriptome axis for PD pathogenesis. Collectively, the mechanistic insights link mitochondrial dysfunction to epigenetic dysregulation in dopaminergic degeneration and offer potential new epigenetic intervention strategies for PD.

SUBMITTER: Huang M

PROVIDER: S-EPMC8492320 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Mitochondrial Dysfunction Induces Epigenetic Dysregulation by H3K27 Hyperacetylation to Perturb Active Enhancers in Parkinson’s Disease Models

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Project description:Mitochondrial Stress-induced H4K12 Hyperacetylation Dysregulates Transcription in Parkinson's Disease

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Mitochondrial Dysfunction Induces Epigenetic Dysregulation by H3K27 Hyperacetylation to Perturb Active Enhancers in Parkinson’s Disease Models

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Project description:Mitochondria are the prime energy source in most eukaryotic cells, but these highly dynamic organelles are also involved in a multitude of cellular events. Disruption of mitochondrial homeostasis and the subsequent mitochondrial dysfunction plays a key role in the pathophysiology of Parkinson's disease (PD). Therefore, maintenance of mitochondrial integrity through different surveillance mechanisms is critical for neuronal survival. Here, we have studied the mitochondrial protein import system in in vitro and in vivo models of PD. Complex I inhibition, a characteristic pathological hallmark in PD, impaired mitochondrial protein import, which was associated with a downregulation of two key components of the system: translocase of the outer membrane 20 (TOM20) and translocase of the inner membrane 23 (TIM23), both in vitro and in vivo. In vitro, those changes were associated with OXPHOS protein downregulation, accumulation of aggregated proteins inside mitochondria and downregulation of mitochondrial chaperones. Most of these pathogenic changes, including mitochondrial dysfunction and dopaminergic cell death, were abrogated by TOM20 or TIM23 overexpression, in vitro. However, in vivo, while TOM20 overexpression exacerbated neurodegeneration in both substantia nigra (SN) pars compacta (pc) and striatum, overexpression of TIM23 partially protected dopaminergic neurons in the SNpc. These results highlight mitochondrial protein import dysfunction and the distinct role of two of their components in the pathogenesis of PD and suggest the need for future studies to further characterize mitochondrial protein import deficit in the context of PD.

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Project description:Mitochondrial impairment is a well-established pathological pathway implicated in Parkinson's disease (PD). Defects of the complex I of the mitochondrial respiratory chain have been found in post-mortem brains from sporadic PD patients. Furthermore, several disease-related genes are linked to mitochondrial pathways, such as PRKN, PINK1, DJ-1 and HTRA2 and are associated with mitochondrial impairment. This phenotype can be caused by the dysfunction of mitochondrial quality control machinery at different levels: molecular, organellar or cellular. Mitochondrial unfolded protein response represents the molecular level and implicates various chaperones and proteases. If the molecular level of quality control is not sufficient, the organellar level is required and involves mitophagy and mitochondrial-derived vesicles to sequester whole dysfunctional organelle or parts of it. Only when the impairment is too severe, does it lead to cell death via apoptosis, which defines the cellular level of quality control. Here, we review how currently known PD-linked genetic variants interfere with different levels of mitochondrial quality control. We discuss the graded risk concept of the most recently identified PARK loci (PARK 17-23) and some susceptibility variants in GBA, LRRK2 and SNCA. Finally, the emerging concept of rare genetic variants in candidates genes for PD, such as HSPA9, TRAP1 and RHOT1, complete the picture of the complex genetic architecture of PD that will direct future precision medicine approaches.

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Project description:UnlabelledMitochondria are highly dynamic, multifunctional organelles. Aside from their major role in energy metabolism, they are also crucial for many cellular processes including neurotransmission, synaptic maintenance, calcium homeostasis, cell death, and neuronal survival.SignificanceIncreasing evidence supports a role for abnormal mitochondrial function in the molecular pathophysiology of Parkinson's disease (PD). For three decades we have known that mitochondrial toxins are capable of producing clinical parkinsonism in humans. PD is the most common neurodegenerative movement disorder that is characterized by the progressive loss of substantia nigra dopaminergic neurons leading to a deficiency of striatal dopamine. Although the neuropathology underlying the disease is well defined, it remains unclear why nigral dopaminergic neurons degenerate and die.Recent advancesMost PD cases are idiopathic, but there are rare familial cases. Mutations in five genes are known to unambiguously cause monogenic familial PD: α-synuclein, parkin, DJ-1, PTEN-induced kinase 1 (PINK1), and leucine-rich repeat kinase 2 (LRRK2). These key molecular players are proteins of seemingly diverse function, but with potentially important roles in mitochondrial maintenance and function. Cell and animal-based genetic models have provided indispensable tools for understanding the molecular basis of PD, and have provided additional evidence implicating mitochondrial dysfunction as a primary pathogenic pathway leading to the demise of dopaminergic neurons in PD.Critical issuesHere, we critically discuss the evidence for mitochondrial dysfunction in genetic animal models of PD, and evaluate whether abnormal mitochondrial function represents a cause or consequence of disease pathogenesis.Future directionsMitochondria may represent a potential target for the development of disease-modifying therapies.

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