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Mitochondrial protein dysfunction in pathogenesis of neurological diseases.

ABSTRACT: Mitochondria are essential organelles for neuronal function and cell survival. Besides the well-known bioenergetics, additional mitochondrial roles in calcium signaling, lipid biogenesis, regulation of reactive oxygen species, and apoptosis are pivotal in diverse cellular processes. The mitochondrial proteome encompasses about 1,500 proteins encoded by both the nuclear DNA and the maternally inherited mitochondrial DNA. Mutations in the nuclear or mitochondrial genome, or combinations of both, can result in mitochondrial protein deficiencies and mitochondrial malfunction. Therefore, mitochondrial quality control by proteins involved in various surveillance mechanisms is critical for neuronal integrity and viability. Abnormal proteins involved in mitochondrial bioenergetics, dynamics, mitophagy, import machinery, ion channels, and mitochondrial DNA maintenance have been linked to the pathogenesis of a number of neurological diseases. The goal of this review is to give an overview of these pathways and to summarize the interconnections between mitochondrial protein dysfunction and neurological diseases.

SUBMITTER: Wang L

PROVIDER: S-EPMC9489860 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Mitochondrial protein dysfunction in pathogenesis of neurological diseases.

Wang Liang L Yang Ziyun Z He Xiumei X Pu Shiming S Yang Cheng C Wu Qiong Q Zhou Zuping Z Cen Xiaobo X Zhao Hongxia H

Frontiers in molecular neuroscience 20220907

Mitochondria are essential organelles for neuronal function and cell survival. Besides the well-known bioenergetics, additional mitochondrial roles in calcium signaling, lipid biogenesis, regulation of reactive oxygen species, and apoptosis are pivotal in diverse cellular processes. The mitochondrial proteome encompasses about 1,500 proteins encoded by both the nuclear DNA and the maternally inherited mitochondrial DNA. Mutations in the nuclear or mitochondrial genome, or combinations of both, c ...[more]

PMID: 36157077

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Project description:BackgroundChronic lung diseases, such as chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) are linked to several mitochondrial alterations. Cigarette smoke (CS) alters the structure and function of mitochondria. OPA1 is the main inner mitochondrial GTPase responsible for the fusion events. OPA1 undergoes proteolytic cleavage from long to short forms during acute stress and mitophagy. However, the exact role of OPA1 isoforms and related proteins during CS-induced mitophagy and COPD is not clear.MethodsLung tissues from non-smokers, smokers, COPD and IPF were used to determine the relative expression of OPA1 and related proteins. Additionally, we used mouse lungs from chronic (6 months) CS exposure to evaluate the status of OPA1. Primary lung fibroblasts from normal and COPD patients and naked mole rat (NMR) lung fibroblasts, human fetal lung fibroblast (HFL1), mouse embryonic fibroblast from wild type (WT), OPA1-/-, MFN1 and MFN2-/- were used to determine the effect of CS on OPA1 isoforms. Various mitochondrial fusion promoters/activators (BGP-15, leflunomide, M1) and fission inhibitor (DRP1) were used to determine their effect on OPA1 status and cigarette smoke extract (CSE)-induced lung epithelial (BEAS2B) cell damage, respectively. Seahorse flux analyzer was used to determine the effect of these compounds in BEAS2B cells with and without CSE exposure.FindingsShort OPA1 isoforms were predominantly detected and significantly increased in COPD subjects. Acute CSE treatment in various cell lines except NMR was found to increase the conversion of long to short OPA1 isoforms. CSE treatment significantly increased mitochondrial stress-related protein SLP2 in all the cells used. OPA1 interacting partners like prohibitins (PHB1 and 2) were also altered depending on the CS exposure. Finally, BGP-15 and leflunomide treatment were able to preserve the long OPA1 isoform in cells treated with CSE.Interpretation/conclusionThe long OPA1 isoform along with SLP2 and prohibitins play a crucial role in CS-induced lung damage, causing mitophagy/mitochondrial dysfunction in COPD, which may be used as a novel therapeutic target in COPD.

Project description:Mitochondria are the repository for various metabolites involved in diverse energy-generating processes, like the TCA cycle, oxidative phosphorylation, and metabolism of amino acids, fatty acids, and nucleotides, which rely significantly on flavoenzymes, such as oxidases, reductases, and dehydrogenases. Flavoenzymes are functionally dependent on biologically active flavin adenine dinucleotide (FAD) or flavin mononucleotide (FMN), which are derived from the dietary component riboflavin, a water soluble vitamin. Riboflavin regulates the structure and function of flavoenzymes through its cofactors FMN and FAD and, thus, protects the cells from oxidative stress and apoptosis. Hence, it is not surprising that any disturbance in riboflavin metabolism and absorption of this vitamin may have consequences on cellular FAD and FMN levels, resulting in mitochondrial dysfunction by reduced energy levels, leading to riboflavin associated disorders, like cataracts, neurodegenerative and cardiovascular diseases, etc. Furthermore, mutations in either nuclear or mitochondrial DNA encoding for flavoenzymes and flavin transporters significantly contribute to the development of various neurological disorders. Moreover, recent studies have evidenced that riboflavin supplementation remarkably improved the clinical symptoms, as well as the biochemical abnormalities, in patients with neuronopathies, like Brown-Vialetto-Van-Laere syndrome (BVVLS) and Fazio-Londe disease. This review presents an updated outlook on the cellular and molecular mechanisms of neurodegenerative disorders in which riboflavin deficiency leads to dysfunction in mitochondrial energy metabolism, and also highlights the significance of riboflavin supplementation in aforementioned disease conditions. Thus, the outcome of this critical assessment may exemplify a new avenue to enhance the understanding of possible mechanisms in the progression of neurodegenerative diseases and may provide new rational approaches of disease surveillance and treatment.

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Mitochondrial protein dysfunction in pathogenesis of neurological diseases.

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Mitochondrial protein dysfunction in pathogenesis of neurological diseases.

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