The decreased expression of mitofusin-1 and increased fission-1 together with alterations in mitochondrial morphology in the kidney of rats with chronic fluorosis may involve elevated oxidative stress

AbstractMitochondria fulfill essential roles in ATP production, metabolic regulation, calcium signaling, generation of reactive oxygen species (ROS) and additional determinants of cellular health. Recent studies have highlighted a role for mitochondria during cell differentiation, including in skin epidermis. The observation of oxidative stress in keratinocytes from Krt16 null mouse skin, a model for pachyonychia congenita (PC)-associated palmoplantar keratoderma, prompted us to examine the role of Keratin (K) 16 protein and its partner K6 in regulating the structure and function of mitochondria. Electron microscopy revealed major anomalies in mitochondrial ultrastructure in late stage, E18.5, Krt6a/Krt6b null embryonic mouse skin. Follow-up studies utilizing biochemical, metabolic, and live imaging readouts showed that, relative to controls, skin keratinocytes null for Krt6a/Krt6b or Krt16 exhibit elevated ROS, reduced mitochondrial respiration, intracellular distribution differences and altered movement of mitochondria within the cell. These findings highlight a novel role for K6 and K16 in regulating mitochondrial morphology, dynamics and function and shed new light on the causes of oxidative stress observed in PC and related keratin-based skin disorders.

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The novel cyclophilin-D-interacting protein FASTKD1 protects cells against oxidative stress-induced cell death

AJP Cell Physiology ◽

10.1152/ajpcell.00471.2018 ◽

2019 ◽

Vol 317 (3) ◽

pp. C584-C599

Author(s):

Kurt D. Marshall ◽

Paula J. Klutho ◽

Lihui Song ◽

Maike Krenz ◽

Christopher P. Baines

Keyword(s):

Oxidative Stress ◽

Cell Death ◽

Mitochondrial Permeability Transition ◽

Permeability Transition ◽

Kinase Domain ◽

Protective Role ◽

Mitochondrial Morphology ◽

Cyclophilin D ◽

Interacting Protein ◽

Mitochondrial Homeostasis

Opening of the mitochondrial permeability transition (MPT) pore leads to necrotic cell death. Excluding cyclophilin D (CypD), the makeup of the MPT pore remains conjecture. The purpose of these experiments was to identify novel MPT modulators by analyzing proteins that associate with CypD. We identified Fas-activated serine/threonine phosphoprotein kinase domain-containing protein 1 (FASTKD1) as a novel CypD interactor. Overexpression of FASTKD1 protected mouse embryonic fibroblasts (MEFs) against oxidative stress-induced reactive oxygen species (ROS) production and cell death, whereas depletion of FASTKD1 sensitized them. However, manipulation of FASTKD1 levels had no effect on MPT responsiveness, Ca2+-induced cell death, or antioxidant capacity. Moreover, elevated FASTKD1 levels still protected against oxidative stress in CypD-deficient MEFs. FASTKD1 overexpression decreased Complex-I-dependent respiration and ΔΨm in MEFs, effects that were abrogated in CypD-null cells. Additionally, overexpression of FASTKD1 in MEFs induced mitochondrial fragmentation independent of CypD, activation of Drp1, and inhibition of autophagy/mitophagy, whereas knockdown of FASTKD1 had the opposite effect. Manipulation of FASTKD1 expression also modified oxidative stress-induced caspase-3 cleavage yet did not alter apoptotic death. Finally, the effects of FASTKD1 overexpression on oxidative stress-induced cell death and mitochondrial morphology were recapitulated in cultured cardiac myocytes. Together, these data indicate that FASTKD1 supports mitochondrial homeostasis and plays a critical protective role against oxidant-induced death.

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Short- and long-term alterations of mitochondrial morphology, dynamics and mtDNA after transient oxidative stress

Mitochondrion ◽

10.1016/j.mito.2008.06.001 ◽

2008 ◽

Vol 8 (4) ◽

pp. 293-304 ◽

Cited By ~ 133

Author(s):

Marina Jendrach ◽

Sören Mai ◽

Sandra Pohl ◽

Monika Vöth ◽

Jürgen Bereiter-Hahn

Keyword(s):

Oxidative Stress ◽

Mitochondrial Morphology ◽

Short And Long Term

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Different molecular mechanisms involved in spontaneous and oxidative stress-induced mitochondrial fragmentation in tripeptidyl peptidase-1 (TPP-1)-deficient fibroblasts

Bioscience Reports ◽

10.1042/bsr20120104 ◽

2013 ◽

Vol 33 (2) ◽

Cited By ~ 7

Author(s):

Guillaume Van Beersel ◽

Eliane Tihon ◽

Stéphane Demine ◽

Isabelle Hamer ◽

Michel Jadot ◽

...

Keyword(s):

Oxidative Stress ◽

Molecular Mechanisms ◽

Morphological Alteration ◽

Neuronal Ceroid Lipofuscinoses ◽

Mitochondrial Morphology ◽

Mitochondrial Fragmentation ◽

Interacting Protein ◽

Mitochondrial Oxidative Stress ◽

Tripeptidyl Peptidase ◽

And Oxidative Stress

NCLs (neuronal ceroid lipofuscinoses) form a group of eight inherited autosomal recessive diseases characterized by the intralysosomal accumulation of autofluorescent pigments, called ceroids. Recent data suggest that the pathogenesis of NCL is associated with the appearance of fragmented mitochondria with altered functions. However, even if an impairement in the autophagic pathway has often been evoked, the molecular mechanisms leading to mitochondrial fragmentation in response to a lysosomal dysfunction are still poorly understood. In this study, we show that fibroblasts that are deficient for the TPP-1 (tripeptidyl peptidase-1), a lysosomal hydrolase encoded by the gene mutated in the LINCL (late infantile NCL, CLN2 form) also exhibit a fragmented mitochondrial network. This morphological alteration is accompanied by an increase in the expression of the protein BNIP3 (Bcl2/adenovirus E1B 19 kDa interacting protein 3) as well as a decrease in the abundance of mitofusins 1 and 2, two proteins involved in mitochondrial fusion. Using RNAi (RNA interference) and quantitative analysis of the mitochondrial morphology, we show that the inhibition of BNIP3 expression does not result in an increase in the reticulation of the mitochondrial population in LINCL cells. However, this protein seems to play a key role in cell response to mitochondrial oxidative stress as it sensitizes mitochondria to antimycin A-induced fragmentation. To our knowledge, our results bring the first evidence of a mechanism that links TPP-1 deficiency and oxidative stress-induced changes in mitochondrial morphology.

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The Characterization of TA-289, a Novel Antifungal from Fusarium sp.

10.26686/wgtn.16992670 ◽

2021 ◽

Author(s):

◽

Natelle C H Quek

Keyword(s):

Oxidative Stress ◽

Reactive Oxygen Species ◽

Cell Cycle ◽

Cell Death ◽

Reactive Oxygen ◽

Chemical Diversity ◽

Mitochondrial Morphology ◽

Ros Production ◽

Oxygen Species ◽

Wild Type

<p>Natural products offer vast structural and chemical diversity highly sought after in drug discovery research. Saccharomyces cerevisiae makes an ideal model eukaryotic organism for drug mode-of-action studies owing to ease of growth, sophistication of genetic tools and overall homology to higher eukaryotes. Equisetin and a closely related novel natural product, TA-289, are cytotoxic to fermenting yeast, but seemingly less so when yeast actively respire. Cell cycle analyses by flow cytometry revealed a cell cycle block at S-G2/M phase caused by TA-289; previously described oxidative stress-inducing compounds causing cell cycle delay led to further investigation in the involvement of equisetin and TA-289 in mitochondrial-mediated generation of reactive oxygen species. Chemical genomic profiling involving genome-wide scans of yeast deletion mutant strains for TA-289 sensitivity revealed sensitization of genes involved in the mitochondria, DNA damage repair and oxidative stress responses, consistent with a possible mechanism-of-action at the mitochondrion. Flow cytometric detection of reactive oxygen species (ROS) generation caused by TA-289 suggests that the compound may induce cell death via ROS production. The generation of a mutant strain resistant to TA-289 also displayed resistance to a known oxidant, H2O2, at concentrations that were cytotoxic to wild-type cells. The resistant mutant displayed a higher basal level of ROS production compared to the wild-type parent, indicating that the resistance mutation led to an up-regulation of antioxidant capacity which provides cell survival in the presence of TA-289. Yeast mitochondrial morphology was visualized by confocal light microscopy, where it was observed that cells treated with TA-289 displayed abnormal mitochondria phenotypes, further indicating that the compound is acting primarily at the mitochondrion. Similar effects observed with equisetin treatment suggest that both compounds share the same mechanism, eliciting cell death via ROS production in the mitochondrial respiratory chain.</p>

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Mitochondrial Dysfunction and Oxidative Stress in Alzheimer’s Disease

Frontiers in Aging Neuroscience ◽

10.3389/fnagi.2021.617588 ◽

2021 ◽

Vol 13 ◽

Cited By ~ 1

Author(s):

Afzal Misrani ◽

Sidra Tabassum ◽

Li Yang

Keyword(s):

Oxidative Stress ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mitochondrial Dysfunction ◽

Mitochondrial Function ◽

Mitochondrial Dynamics ◽

Mitochondrial Morphology ◽

Therapeutic Approaches ◽

The Impact ◽

And Oxidative Stress

Mitochondria play a pivotal role in bioenergetics and respiratory functions, which are essential for the numerous biochemical processes underpinning cell viability. Mitochondrial morphology changes rapidly in response to external insults and changes in metabolic status via fission and fusion processes (so-called mitochondrial dynamics) that maintain mitochondrial quality and homeostasis. Damaged mitochondria are removed by a process known as mitophagy, which involves their degradation by a specific autophagosomal pathway. Over the last few years, remarkable efforts have been made to investigate the impact on the pathogenesis of Alzheimer’s disease (AD) of various forms of mitochondrial dysfunction, such as excessive reactive oxygen species (ROS) production, mitochondrial Ca2+ dyshomeostasis, loss of ATP, and defects in mitochondrial dynamics and transport, and mitophagy. Recent research suggests that restoration of mitochondrial function by physical exercise, an antioxidant diet, or therapeutic approaches can delay the onset and slow the progression of AD. In this review, we focus on recent progress that highlights the crucial role of alterations in mitochondrial function and oxidative stress in the pathogenesis of AD, emphasizing a framework of existing and potential therapeutic approaches.

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Glucagon-Like Peptide-1 Receptor Agonist Ameliorates 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine (MPTP) Neurotoxicity Through Enhancing Mitophagy Flux and Reducing α-Synuclein and Oxidative Stress

Frontiers in Molecular Neuroscience ◽

10.3389/fnmol.2021.697440 ◽

2021 ◽

Vol 14 ◽

Author(s):

Tsu-Kung Lin ◽

Kai-Jung Lin ◽

Hung-Yu Lin ◽

Kai-Lieh Lin ◽

Min-Yu Lan ◽

...

Keyword(s):

Oxidative Stress ◽

Substantia Nigra ◽

Mitochondrial Dysfunction ◽

Mitochondrial Fusion ◽

Motor Dysfunction ◽

Mitochondrial Morphology ◽

Autophagy Flux ◽

Neuroprotective Effects ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

Parkinson disease (PD) is the second most common neurodegenerative disease without known disease modification therapy to slow down disease progression. This disease has pathological features of Lewy bodies with α-synuclein aggregation being the major component and selective dopaminergic neuronal loss over the substantia nigra. Although the exact etiology is still unknown, mitochondrial dysfunction has been shown to be central in PD pathophysiology. Type 2 diabetes mellitus has recently been connected to PD, and anti-diabetic drugs, such as glucagon-like peptide-1 receptor agonists (GLP-1RAs), have been shown to possess neuroprotective effects in PD animal models. The GLP-1RA liraglutide is currently under a phase 2 clinical trial to measure its effect on motor and non-motor symptoms in PD patients. In this study, we used an acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD to test the possible mechanism of the GLP-1RA liraglutide in the pathogenesis of PD. We show that the neurobehavioral and motor dysfunction caused by the mitochondrial complex I inhibitor, MPTP, can be partially reversed by liraglutide. The GLP-1RA can protect mice from apoptosis of substantia nigra neurons induced by MPTP. MPTP treatment led to imbalanced mitochondrial fusion and fission dynamics, altered mitochondrial morphology, impeded autophagy flux, increased α-synuclein accumulation, and elevated oxidative stress. Specifically, the normalizing of mitochondrial fusion-fission dynamic-related proteins and enhancement of autophagy flux after administration of liraglutide is associated with improving neuronal survival. This suggests that GLP-1RAs may provide potential beneficial effects for PD caused by mitochondrial dysfunction through improvement of mitochondrial morphology balance and enhancing damaged organelle degradation.

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Faculty Opinions recommendation of Combined mineralocorticoid and glucocorticoid deficiency is caused by a novel founder nicotinamide nucleotide transhydrogenase mutation that alters mitochondrial morphology and increases oxidative stress.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.725565005.793507878 ◽

2015 ◽

Author(s):

Karen Chapman

Keyword(s):

Oxidative Stress ◽

Mitochondrial Morphology ◽

Nicotinamide Nucleotide Transhydrogenase ◽

Glucocorticoid Deficiency

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Oxidative stress-induced mitochondrial fragmentation and movement in skeletal muscle myoblasts

AJP Cell Physiology ◽

10.1152/ajpcell.00017.2014 ◽

2014 ◽

Vol 306 (12) ◽

pp. C1176-C1183 ◽

Cited By ~ 53

Author(s):

Sobia Iqbal ◽

David A. Hood

Keyword(s):

Oxidative Stress ◽

Unfolded Protein Response ◽

Mitochondrial Morphology ◽

Related Protein ◽

Mitochondrial Fragmentation ◽

Signaling Mechanism ◽

Unfolded Protein ◽

Mitochondrial Motility ◽

And Function ◽

Protein Response

Mitochondria are dynamic organelles, capable of altering their morphology and function. However, the mechanisms governing these changes have not been fully elucidated, particularly in muscle cells. We demonstrated that oxidative stress with H2O2 resulted in a 41% increase in fragmentation of the mitochondrial reticulum in myoblasts within 3 h of exposure, an effect that was preceded by a reduction in membrane potential. Using live cell imaging, we monitored mitochondrial motility and found that oxidative stress resulted in a 30% reduction in the average velocity of mitochondria. This was accompanied by parallel reductions in both organelle fission and fusion. The attenuation in mitochondrial movement was abolished by the addition of N-acetylcysteine. To investigate whether H2O2-induced fragmentation was mediated by dynamin-related protein 1, we incubated cells with mDivi1, an inhibitor of dynamin-related protein 1 translocation to mitochondria. mDivi1 attenuated oxidative stress-induced mitochondrial fragmentation by 27%. Moreover, we demonstrated that exposure to H2O2 upregulated endoplasmic reticulum-unfolded protein response markers before the initiation of mitophagy signaling and the mitochondrial-unfolded protein response. These findings indicate that oxidative stress is a vital signaling mechanism in the regulation of mitochondrial morphology and motility.

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Inhibition of complex I of the electron transport chain causes O2−·-mediated mitochondrial outgrowth

AJP Cell Physiology ◽

10.1152/ajpcell.00607.2004 ◽

2005 ◽

Vol 288 (6) ◽

pp. C1440-C1450 ◽

Cited By ~ 200

Author(s):

Werner J. H. Koopman ◽

Sjoerd Verkaart ◽

Henk-Jan Visch ◽

Francois H. van der Westhuizen ◽

Michael P. Murphy ◽

...

Keyword(s):

Oxidative Stress ◽

Lipid Peroxidation ◽

Complex I ◽

Mammalian Cells ◽

Automated Analysis ◽

Mitochondrial Morphology ◽

Twofold Increase ◽

Transport Chain ◽

Rotenone Treatment ◽

The Relationship

Recent evidence indicates that oxidative stress is central to the pathogenesis of a wide variety of degenerative diseases, aging, and cancer. Oxidative stress occurs when the delicate balance between production and detoxification of reactive oxygen species is disturbed. Mammalian cells respond to this condition in several ways, among which is a change in mitochondrial morphology. In the present study, we have used rotenone, an inhibitor of complex I of the respiratory chain, which is thought to increase mitochondrial O2−· production, and mitoquinone (MitoQ), a mitochondria-targeted antioxidant, to investigate the relationship between mitochondrial O2−· production and morphology in human skin fibroblasts. Video-rate confocal microscopy of cells pulse loaded with the mitochondria-specific cation rhodamine 123, followed by automated analysis of mitochondrial morphology, revealed that chronic rotenone treatment (100 nM, 72 h) significantly increased mitochondrial length and branching without changing the number of mitochondria per cell. In addition, this treatment caused a twofold increase in lipid peroxidation as determined with C11-BODIPY581/591. Finally, digital imaging microscopy of cells loaded with hydroethidine, which is oxidized by O2−· to yield fluorescent ethidium, revealed that chronic rotenone treatment caused a twofold increase in the rate of O2−· production. MitoQ (10 nM, 72 h) did not interfere with rotenone-induced ethidium formation but abolished rotenone-induced outgrowth and lipid peroxidation. These findings show that increased mitochondrial O2−· production as a consequence of, for instance, complex I inhibition leads to mitochondrial outgrowth and that MitoQ acts downstream of this O2−· to prevent alterations in mitochondrial morphology.

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