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20 pages, 3808 KiB

Open AccessArticle

Mitochondrial Dysfunction in Spinocerebellar Ataxia Type 3 Is Linked to VDAC1 Deubiquitination

by Tina Harmuth, Jonasz J. Weber, Anna J. Zimmer, Anna S. Sowa, Jana Schmidt, Julia C. Fitzgerald, Ludger Schöls, Olaf Riess and Jeannette Hübener-Schmid

Int. J. Mol. Sci. 2022, 23(11), 5933; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23115933 - 25 May 2022

Cited by 8 | Viewed by 2481

Abstract

Dysfunctional mitochondria are linked to several neurodegenerative diseases. Metabolic defects, a symptom which can result from dysfunctional mitochondria, are also present in spinocerebellar ataxia type 3 (SCA3), also known as Machado–Joseph disease, the most frequent, dominantly inherited neurodegenerative ataxia worldwide. Mitochondrial dysfunction has [...] Read more.

Dysfunctional mitochondria are linked to several neurodegenerative diseases. Metabolic defects, a symptom which can result from dysfunctional mitochondria, are also present in spinocerebellar ataxia type 3 (SCA3), also known as Machado–Joseph disease, the most frequent, dominantly inherited neurodegenerative ataxia worldwide. Mitochondrial dysfunction has been reported for several neurodegenerative disorders and ataxin-3 is known to deubiquitinylate parkin, a key protein required for canonical mitophagy. In this study, we analyzed mitochondrial function and mitophagy in a patient-derived SCA3 cell model. Human fibroblast lines isolated from SCA3 patients were immortalized and characterized. SCA3 patient fibroblasts revealed circular, ring-shaped mitochondria and featured reduced OXPHOS complexes, ATP production and cell viability. We show that wildtype ataxin-3 deubiquitinates VDAC1 (voltage-dependent anion channel 1), a member of the mitochondrial permeability transition pore and a parkin substrate. In SCA3 patients, VDAC1 deubiquitination and parkin recruitment to the depolarized mitochondria is inhibited. Increased p62-linked mitophagy, autophagosome formation and autophagy is observed under disease conditions, which is in line with mitochondrial fission. SCA3 fibroblast lines demonstrated a mitochondrial phenotype and dysregulation of parkin-VDAC1-mediated mitophagy, thereby promoting mitochondrial quality control via alternative pathways. Full article

(This article belongs to the Special Issue Mitochondrial Function in Neurodegenerative Diseases)

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16 pages, 1836 KiB

Open AccessArticle

Mitochondrial and Neuronal Dysfunctions in L1 Mutant Mice

by Ludovica Congiu, Viviana Granato, Gabriele Loers, Ralf Kleene and Melitta Schachner

Int. J. Mol. Sci. 2022, 23(8), 4337; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23084337 - 14 Apr 2022

Cited by 7 | Viewed by 1901

Abstract

Adhesion molecules regulate cell proliferation, migration, survival, neuritogenesis, synapse formation and synaptic plasticity during the nervous system’s development and in the adult. Among such molecules, the neural cell adhesion molecule L1 contributes to these functions during development, and in synapse formation, synaptic plasticity [...] Read more.

Adhesion molecules regulate cell proliferation, migration, survival, neuritogenesis, synapse formation and synaptic plasticity during the nervous system’s development and in the adult. Among such molecules, the neural cell adhesion molecule L1 contributes to these functions during development, and in synapse formation, synaptic plasticity and regeneration after trauma. Proteolytic cleavage of L1 by different proteases is essential for these functions. A proteolytic fragment of 70 kDa (abbreviated L1-70) comprising part of the extracellular domain and the transmembrane and intracellular domains was shown to interact with mitochondrial proteins and is suggested to be involved in mitochondrial functions. To further determine the role of L1-70 in mitochondria, we generated two lines of gene-edited mice expressing full-length L1, but no or only low levels of L1-70. We showed that in the absence of L1-70, mitochondria in cultured cerebellar neurons move more retrogradely and exhibit reduced mitochondrial membrane potential, impaired Complex I activity and lower ATP levels compared to wild-type littermates. Neither neuronal migration, neuronal survival nor neuritogenesis in these mutants were stimulated with a function-triggering L1 antibody or with small agonistic L1 mimetics. These results suggest that L1-70 is important for mitochondrial homeostasis and that its absence contributes to the L1 syndrome phenotypes. Full article

(This article belongs to the Special Issue Mitochondrial Function in Neurodegenerative Diseases)

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20 pages, 2774 KiB

Open AccessArticle

Effects of Pesticides on Longevity and Bioenergetics in Invertebrates—The Impact of Polyphenolic Metabolites

by Fabian Schmitt, Lukas Babylon, Fabian Dieter and Gunter P. Eckert

Int. J. Mol. Sci. 2021, 22(24), 13478; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222413478 - 15 Dec 2021

Cited by 5 | Viewed by 3157

Abstract

Environmentally hazardous substances such as pesticides are gaining increasing interest in agricultural and nutritional research. This study aims to investigate the impact of these compounds on the healthspan and mitochondrial functions in an invertebrate in vivo model and in vitro in SH-SY5Y neuroblastoma [...] Read more.

Environmentally hazardous substances such as pesticides are gaining increasing interest in agricultural and nutritional research. This study aims to investigate the impact of these compounds on the healthspan and mitochondrial functions in an invertebrate in vivo model and in vitro in SH-SY5Y neuroblastoma cells, and to investigate the potential of polyphenolic metabolites to compensate for potential impacts. Wild-type nematodes (Caenorhabditis elegans, N2) were treated with pesticides such as pyraclostrobin (Pyr), glyphosate (Gly), or fluopyram (Fluo). The lifespans of the nematodes under heat stress conditions (37 °C) were determined, and the chemotaxis was assayed. Energetic metabolites, including adenosine triphosphate (ATP), lactate, and pyruvate, were analyzed in lysates of nematodes and cells. Genetic expression patterns of several genes associated with lifespan determination and mitochondrial parameters were assessed via qRT-PCR. After incubation with environmentally hazardous substances, nematodes were incubated with a pre-fermented polyphenol mixture (Rechtsregulat^®Bio, RR) or protocatechuic acid (PCA) to determine heat stress resistance. Treatment with Pyr, Glyph and Fluo leads to dose-dependently decreased heat stress resistance, which was significantly improved by RR and PCA. The chemotaxes of the nematodes were not affected by pesticides. ATP levels were not significantly altered by the pesticides, except for Pyr, which increased ATP levels after 48 h leads. The gene expression of healthspan and mitochondria-associated genes were diversely affected by the pesticides, while Pyr led to an overall decrease of mRNA levels. Over time, the treatment of nematodes leads to a recovery of the nematodes on the mitochondrial level but not on stress resistance on gene expression. Fermented extracts of fruits and vegetables and phenolic metabolites such as PCA seem to have the potential to recover the vitality of C. elegans after damage caused by pesticides. Full article

(This article belongs to the Special Issue Mitochondrial Function in Neurodegenerative Diseases)

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13 pages, 2954 KiB

Open AccessArticle

Korean Red Ginseng Improves Astrocytic Mitochondrial Function by Upregulating HO-1-Mediated AMPKα–PGC-1α–ERRα Circuit after Traumatic Brain Injury

by Minsu Kim, Joohwan Kim, Sunhong Moon, Bo Young Choi, Sueun Kim, Hui Su Jeon, Sang Won Suh, Young-Myeong Kim and Yoon Kyung Choi

Int. J. Mol. Sci. 2021, 22(23), 13081; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222313081 - 03 Dec 2021

Cited by 10 | Viewed by 1971

Abstract

Heme oxygenase-1 (HO-1) exerts beneficial effects, including angiogenesis and energy metabolism via the peroxisome proliferator-activating receptor-γ coactivator-1α (PGC-1α)–estrogen-related receptor α (ERRα) pathway in astrocytes. However, the role of Korean red ginseng extract (KRGE) in HO-1-mediated mitochondrial function in traumatic brain injury (TBI) is [...] Read more.

Heme oxygenase-1 (HO-1) exerts beneficial effects, including angiogenesis and energy metabolism via the peroxisome proliferator-activating receptor-γ coactivator-1α (PGC-1α)–estrogen-related receptor α (ERRα) pathway in astrocytes. However, the role of Korean red ginseng extract (KRGE) in HO-1-mediated mitochondrial function in traumatic brain injury (TBI) is not well-elucidated. We found that HO-1 was upregulated in astrocytes located in peri-injured brain regions after a TBI, following exposure to KRGE. Experiments with pharmacological inhibitors and target-specific siRNAs revealed that HO-1 levels highly correlated with increased AMP-activated protein kinase α (AMPKα) activation, which led to the PGC-1α-ERRα axis-induced increases in mitochondrial functions (detected based on expression of cytochrome c oxidase subunit 2 (MTCO2) and cytochrome c as well as O₂ consumption and ATP production). Knockdown of ERRα significantly reduced the p-AMPKα/AMPKα ratio and PGC-1α expression, leading to AMPKα–PGC-1α–ERRα circuit formation. Inactivation of HO by injecting the HO inhibitor Sn(IV) protoporphyrin IX dichloride diminished the expression of p-AMPKα, PGC-1α, ERRα, MTCO2, and cytochrome c in the KRGE-administered peri-injured region of a brain subjected to TBI. These data suggest that KRGE enhanced astrocytic mitochondrial function via a HO-1-mediated AMPKα–PGC-1α–ERRα circuit and consequent oxidative phosphorylation, O₂ consumption, and ATP production. This circuit may play an important role in repairing neurovascular function after TBI in the peri-injured region by stimulating astrocytic mitochondrial biogenesis. Full article

(This article belongs to the Special Issue Mitochondrial Function in Neurodegenerative Diseases)

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16 pages, 4212 KiB

Open AccessArticle

1,5-Anhydro-D-fructose Protects against Rotenone-Induced Neuronal Damage In Vitro through Mitochondrial Biogenesis

by Yuki Kasamo, Kiyoshi Kikuchi, Munekazu Yamakuchi, Shotaro Otsuka, Seiya Takada, Yuki Kambe, Takashi Ito, Ko-ichi Kawahara, Kazunori Arita, Koji Yoshimoto and Ikuro Maruyama

Int. J. Mol. Sci. 2021, 22(18), 9941; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22189941 - 14 Sep 2021

Cited by 3 | Viewed by 2684

Abstract

Mitochondrial functional abnormalities or quantitative decreases are considered to be one of the most plausible pathogenic mechanisms of Parkinson’s disease (PD). Thus, mitochondrial complex inhibitors are often used for the development of experimental PD. In this study, we used rotenone to create in [...] Read more.

Mitochondrial functional abnormalities or quantitative decreases are considered to be one of the most plausible pathogenic mechanisms of Parkinson’s disease (PD). Thus, mitochondrial complex inhibitors are often used for the development of experimental PD. In this study, we used rotenone to create in vitro cell models of PD, then used these models to investigate the effects of 1,5-anhydro-D-fructose (1,5-AF), a monosaccharide with protective effects against a range of cytotoxic substances. Subsequently, we investigated the possible mechanisms of these protective effects in PC12 cells. The protection of 1,5-AF against rotenone-induced cytotoxicity was confirmed by increased cell viability and longer dendritic lengths in PC12 and primary neuronal cells. Furthermore, in rotenone-treated PC12 cells, 1,5-AF upregulated peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) expression and enhanced its deacetylation, while increasing AMP-activated protein kinase (AMPK) phosphorylation. 1,5-AF treatment also increased mitochondrial activity in these cells. Moreover, PGC-1α silencing inhibited the cytoprotective and mitochondrial biogenic effects of 1,5-AF in PC12 cells. Therefore, 1,5-AF may activate PGC-1α through AMPK activation, thus leading to mitochondrial biogenic and cytoprotective effects. Together, our results suggest that 1,5-AF has therapeutic potential for development as a treatment for PD. Full article

(This article belongs to the Special Issue Mitochondrial Function in Neurodegenerative Diseases)

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15 pages, 3355 KiB

Open AccessArticle

High-Resolution Respirometry Reveals MPP⁺ Mitochondrial Toxicity Mechanism in a Cellular Model of Parkinson’s Disease

by Pierpaolo Risiglione, Loredana Leggio, Salvatore A. M. Cubisino, Simona Reina, Greta Paternò, Bianca Marchetti, Andrea Magrì, Nunzio Iraci and Angela Messina

Int. J. Mol. Sci. 2020, 21(21), 7809; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21217809 - 22 Oct 2020

Cited by 34 | Viewed by 4596

Abstract

MPP⁺ is the active metabolite of MPTP, a molecule structurally similar to the herbicide Paraquat, known to injure the dopaminergic neurons of the nigrostriatal system in Parkinson’s disease models. Within the cells, MPP⁺ accumulates in mitochondria where it inhibits complex I [...] Read more.

MPP⁺ is the active metabolite of MPTP, a molecule structurally similar to the herbicide Paraquat, known to injure the dopaminergic neurons of the nigrostriatal system in Parkinson’s disease models. Within the cells, MPP⁺ accumulates in mitochondria where it inhibits complex I of the electron transport chain, resulting in ATP depletion and neuronal impairment/death. So far, MPP⁺ is recognized as a valuable tool to mimic dopaminergic degeneration in various cell lines. However, despite a large number of studies, a detailed characterization of mitochondrial respiration in neuronal cells upon MPP⁺ treatment is still missing. By using high-resolution respirometry, we deeply investigated oxygen consumption related to each respiratory state in differentiated neuroblastoma cells exposed to the neurotoxin. Our results indicated the presence of extended mitochondrial damage at the inner membrane level, supported by increased LEAK respiration, and a drastic drop in oxygen flow devoted to ADP phosphorylation in respirometry measurements. Furthermore, prior to complex I inhibition, an enhancement of complex II activity was observed, suggesting the occurrence of some compensatory effect. Overall our findings provide a mechanistic insight on the mitochondrial toxicity mediated by MPP⁺, relevant for the standardization of studies that employ this neurotoxin as a disease model. Full article

(This article belongs to the Special Issue Mitochondrial Function in Neurodegenerative Diseases)

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Review

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18 pages, 1456 KiB

Open AccessReview

Current Concepts on Genetic Aspects of Mitochondrial Dysfunction in Amyotrophic Lateral Sclerosis

by Milena Jankovic, Ivana Novakovic, Phepy Gamil Anwar Dawod, Ayman Gamil Anwar Dawod, Aleksandra Drinic, Fayda I. Abdel Motaleb, Sinisa Ducic and Dejan Nikolic

Int. J. Mol. Sci. 2021, 22(18), 9832; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22189832 - 11 Sep 2021

Cited by 20 | Viewed by 3035

Abstract

Amyotrophic Lateral Sclerosis (ALS), neurodegenerative motor neuron disorder is characterized as multisystem disease with important contribution of genetic factors. The etiopahogenesis of ALS is not fully elucidate, but the dominant theory at present relates to RNA processing, as well as protein aggregation and [...] Read more.

Amyotrophic Lateral Sclerosis (ALS), neurodegenerative motor neuron disorder is characterized as multisystem disease with important contribution of genetic factors. The etiopahogenesis of ALS is not fully elucidate, but the dominant theory at present relates to RNA processing, as well as protein aggregation and miss-folding, oxidative stress, glutamate excitotoxicity, inflammation and epigenetic dysregulation. Additionally, as mitochondria plays a leading role in cellular homeostasis maintenance, a rising amount of evidence indicates mitochondrial dysfunction as a substantial contributor to disease onset and progression. The aim of this review is to summarize most relevant findings that link genetic factors in ALS pathogenesis with different mechanisms with mitochondrial involvement (respiratory chain, OXPHOS control, calcium buffering, axonal transport, inflammation, mitophagy, etc.). We highlight the importance of a widening perspective for better understanding overlapping pathophysiological pathways in ALS and neurodegeneration in general. Finally, current and potentially novel therapies, especially gene specific therapies, targeting mitochondrial dysfunction are discussed briefly. Full article

(This article belongs to the Special Issue Mitochondrial Function in Neurodegenerative Diseases)

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18 pages, 1732 KiB

Open AccessReview

The Link between Oxidative Stress, Redox Status, Bioenergetics and Mitochondria in the Pathophysiology of ALS

by Elena Obrador, Rosario Salvador-Palmer, Rafael López-Blanch, Ali Jihad-Jebbar, Soraya L. Vallés and José M. Estrela

Int. J. Mol. Sci. 2021, 22(12), 6352; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22126352 - 14 Jun 2021

Cited by 45 | Viewed by 4467

Abstract

Amyotrophic lateral sclerosis (ALS) is the most common neurodegenerative disease of the motor system. It is characterized by the degeneration of both upper and lower motor neurons, which leads to muscle weakness and paralysis. ALS is incurable and has a bleak prognosis, with [...] Read more.

Amyotrophic lateral sclerosis (ALS) is the most common neurodegenerative disease of the motor system. It is characterized by the degeneration of both upper and lower motor neurons, which leads to muscle weakness and paralysis. ALS is incurable and has a bleak prognosis, with median survival of 3–5 years after the initial symptomatology. In ALS, motor neurons gradually degenerate and die. Many features of mitochondrial dysfunction are manifested in neurodegenerative diseases, including ALS. Mitochondria have shown to be an early target in ALS pathophysiology and contribute to disease progression. Disruption of their axonal transport, excessive generation of reactive oxygen species, disruption of the mitochondrial structure, dynamics, mitophagy, energy production, calcium buffering and apoptotic triggering have all been directly involved in disease pathogenesis and extensively reported in ALS patients and animal model systems. Alterations in energy production by motor neurons, which severely limit their survival capacity, are tightly linked to the redox status and mitochondria. The present review focuses on this link. Placing oxidative stress as a main pathophysiological mechanism, the molecular interactions and metabolic flows involved are analyzed. This leads to discussing potential therapeutic approaches targeting mitochondrial biology to slow disease progression. Full article

(This article belongs to the Special Issue Mitochondrial Function in Neurodegenerative Diseases)

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