bims-mitinf 2019-02-03 papers

Issue of 2019‒02‒03
four papers selected by
Prafull Kumar Singh
University of Freiburg Medical Center

Cells. 2019 Jan 29. pii: E100. [Epub ahead of print]8(2):

Mitochondrial DNA Integrity: Role in Health and Disease.

As the primary cellular location for respiration and energy production, mitochondria serve in a critical capacity to the cell. Yet, by virtue of this very function of respiration, mitochondria are subject to constant oxidative stress that can damage one of the unique features of this organelle, its distinct genome. Damage to mitochondrial DNA (mtDNA) and loss of mitochondrial genome integrity is increasingly understood to play a role in the development of both severe early-onset maladies and chronic age-related diseases. In this article, we review the processes by which mtDNA integrity is maintained, with an emphasis on the repair of oxidative DNA lesions, and the cellular consequences of diminished mitochondrial genome stability.

Keywords: aging; base excision repair; metabolic syndrome; mitochondrial DNA; neurodegenerative diseases

DOI: https://doi.org/10.3390/cells8020100

Trends Genet. 2019 Jan 25. pii: S0168-9525(19)30002-2. [Epub ahead of print]

Mechanisms of Mitochondrial DNA Deletion Formation.

Nadee Nissanka, Michal Minczuk, Carlos T Moraes.

Mitochondrial DNA (mtDNA) encodes a subset of genes which are essential for oxidative phosphorylation. Deletions in the mtDNA can ablate a number of these genes and result in mitochondrial dysfunction, which is associated with bona fide mitochondrial disorders. Although mtDNA deletions are thought to occur as a result of replication errors or following double-strand breaks, the exact mechanism(s) behind deletion formation have yet to be determined. In this review we discuss the current knowledge about the fate of mtDNA following double-strand breaks, including the molecular players which mediate the degradation of linear mtDNA fragments and possible mechanisms of recircularization. We propose that mtDNA deletions formed from replication errors versus following double-strand breaks can be mediated by separate pathways.

Keywords: double-strand breaks; mitochondrial DNA; mitochondrial DNA deletions; replication

DOI: https://doi.org/10.1016/j.tig.2019.01.001

Mol Brain. 2019 01 28. 12(1): 8

Quantitative profiling brain proteomes revealed mitochondrial dysfunction in Alzheimer's disease.

Sunil S Adav, Jung Eun Park, Siu Kwan Sze.

Mitochondrial dysfunction is a key feature in both aging and neurodegenerative diseases including Alzheimer's disease (AD), but the molecular signature that distinguishes pathological changes in the AD from healthy aging in the brain mitochondria remain poorly understood. In order to unveil AD specific mitochondrial dysfunctions, this study adopted a discovery-driven approach with isobaric tag for relative and absolute quantitation (iTRAQ) and label-free quantitative proteomics, and profiled the mitochondrial proteomes in human brain tissues of healthy and AD individuals. LC-MS/MS-based iTRAQ quantitative proteomics approach revealed differentially altered mitochondriomes that distinguished the AD's pathophysiology-induced from aging-associated changes. Our results showed that dysregulated mitochondrial complexes including electron transport chain (ETC) and ATP-synthase are the potential driver for pathology of the AD. The iTRAQ results were cross-validated with independent label-free quantitative proteomics experiments to confirm that the subunit of electron transport chain complex I, particularly NDUFA4 and NDUFA9 were altered in AD patients, suggesting destabilization of the junction between membrane and matrix arms of mitochondrial complex I impacted the mitochondrial functions in the AD. iTRAQ quantitative proteomics of brain mitochondriomes revealed disparity in healthy aging and age-dependent AD.

Keywords: Alzheimer’s disease; Complex I; Mitochondrial dysfunction; Mitochondriome; Neurodegenerative diseases; Proteomics; iTRAQ

DOI: https://doi.org/10.1186/s13041-019-0430-y

Redox Biol. 2019 Jan 23. pii: S2213-2317(18)31288-6. [Epub ahead of print]21 101120

Mst1 inhibition attenuates non-alcoholic fatty liver disease via reversing Parkin-related mitophagy.

Tao Zhou, Ling Chang, Yi Luo, Ying Zhou, Jianjun Zhang.

Obesity-related non-alcoholic fatty liver disease (NAFLD) is connected with mitochondrial stress and hepatocyte apoptosis. Parkin-related mitophagy sustains mitochondrial homeostasis and hepatocyte viability. However, the contribution and regulatory mechanisms of Parkin-related mitophagy in NAFLD are incompletely understood. Macrophage stimulating 1 (Mst1) is a novel mitophagy upstream regulator which excerbates heart and cancer apoptosisn via repressing mitophagy activity. The aim of our study is to explore whether Mst1 contributes to NAFLD via disrupting Parkin-related mitophagy. A NAFLD model was generated in wild-type (WT) mice and Mst1 knockout (Mst1-KO) mice using high-fat diet (HFD). Cell experiments were conducted via palmitic acid (PA) treatment in the primary hepatocytes. The results in our study demonstrated that Mst1 was significantly upregulated in HFD-treated livers. Genetic ablation of Mst1 attenuated HFD-mediated hepatic injury and sustained hepatocyte viability. Functional studies illustrated that Mst1 knockdown reversed Parkin-related mitophagy and the latter protected mitochondria and hepatocytes against HFD challenge. Besides, we further figured out that Mst1 modulated Parkin expression via the AMPK pathway; blockade of AMPK repressed Parkin-related mitophagy and recalled hepatocytes mitochondrial apoptosis. Altogether, our data identified that NAFLD was closely associated with the defective Parkin-related mitophagy due to Mst1 upregulation. This finding may pave the road to new therapeutic modalities for the treatment of fatty liver disease.

Keywords: Mitochondrial damage; Mst1; Non-alcoholic fatty liver disease; Parkin-related mitophagy

DOI: https://doi.org/10.1016/j.redox.2019.101120