Simulation Study on the Balance of Glycolytic ATP Production and Oxidative Phosphorylation in Embryonic and Adult Ventricular Cells

Mitochondrial diseases are a heterogeneous group of diseases resulting from energy deficit and reduced adenosine triphosphate (ATP) production due to impaired oxidative phosphorylation. The manifestation of mitochondrial disease is usually multi-organ. Epilepsy is one of the most common manifestations of diseases resulting from mitochondrial dysfunction, especially in children. The onset of epilepsy is associated with poor prognosis, while its treatment is very challenging, which further adversely affects the course of these disorders. Fortunately, our knowledge of mitochondrial diseases is still growing, which gives hope for patients to improve their condition in the future. The paper presents the pathophysiology, clinical picture and treatment options for epilepsy in patients with mitochondrial disease.

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Dual Mutations Reveal Interactions Between Components of Oxidative Phosphorylation in Kluyveromyces lactis

Genetics ◽

10.1093/genetics/159.3.929 ◽

2001 ◽

Vol 159 (3) ◽

pp. 929-938

Author(s):

G D Clark-Walker ◽

X J Chen

Keyword(s):

Electron Transport ◽

Oxidative Phosphorylation ◽

Atp Synthase ◽

Kluyveromyces Lactis ◽

Mitochondrial Protein ◽

Proton Pumping ◽

Nuclear Genes ◽

Suppressor Activity ◽

Inner Membrane ◽

Atp Production

Abstract Loss of mtDNA or mitochondrial protein synthesis cannot be tolerated by wild-type Kluyveromyces lactis. The mitochondrial function responsible for ρ0-lethality has been identified by disruption of nuclear genes encoding electron transport and F0-ATP synthase components of oxidative phosphorylation. Sporulation of diploid strains heterozygous for disruptions in genes for the two components of oxidative phosphorylation results in the formation of nonviable spores inferred to contain both disruptions. Lethality of spores is thought to result from absence of a transmembrane potential, ΔΨ, across the mitochondrial inner membrane due to lack of proton pumping by the electron transport chain or reversal of F1F0-ATP synthase. Synergistic lethality, caused by disruption of nuclear genes, or ρ0-lethality can be suppressed by the atp2.1 mutation in the β-subunit of F1-ATPase. Suppression is viewed as occurring by an increased hydrolysis of ATP by mutant F1, allowing sufficient electrogenic exchange by the translocase of ADP in the matrix for ATP in the cytosol to maintain ΔΨ. In addition, lethality of haploid strains with a disruption of AAC encoding the ADP/ATP translocase can be suppressed by atp2.1. In this case suppression is considered to occur by mutant F1 acting in the forward direction to partially uncouple ATP production, thereby stimulating respiration and relieving detrimental hyperpolarization of the inner membrane. Participation of the ADP/ATP translocase in suppression of ρ0-lethality is supported by the observation that disruption of AAC abolishes suppressor activity of atp2.1.

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Gene by environmental interactions affecting oxidative phosphorylation and thermal sensitivity

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00008.2016 ◽

2016 ◽

Vol 311 (1) ◽

pp. R157-R165 ◽

Cited By ~ 13

Author(s):

Tara Z. Baris ◽

Pierre U. Blier ◽

Nicolas Pichaud ◽

Douglas L. Crawford ◽

Marjorie F. Oleksiak

Keyword(s):

Oxidative Phosphorylation ◽

Complex I ◽

Thermal Sensitivity ◽

Single Species ◽

Mitochondrial Haplotype ◽

Acclimation Temperature ◽

Atp Production ◽

Acute Response ◽

Relative Contribution ◽

Mitochondrial Genotype

The oxidative phosphorylation (OxPhos) pathway is responsible for most aerobic ATP production and is the only metabolic pathway with proteins encoded by both nuclear and mitochondrial genomes. In studies examining mitonuclear interactions among distant populations within a species or across species, the interactions between these two genomes can affect metabolism, growth, and fitness, depending on the environment. However, there is little data on whether these interactions impact natural populations within a single species. In an admixed Fundulus heteroclitus population with northern and southern mitochondrial haplotypes, there are significant differences in allele frequencies associated with mitochondrial haplotype. In this study, we investigate how mitochondrial haplotype and any associated nuclear differences affect six OxPhos parameters within a population. The data demonstrate significant OxPhos functional differences between the two mitochondrial genotypes. These differences are most apparent when individuals are acclimated to high temperatures with the southern mitochondrial genotype having a large acute response and the northern mitochondrial genotype having little, if any acute response. Furthermore, acute temperature effects and the relative contribution of Complex I and II depend on acclimation temperature: when individuals are acclimated to 12°C, the relative contribution of Complex I increases with higher acute temperatures, whereas at 28°C acclimation, the relative contribution of Complex I is unaffected by acute temperature change. These data demonstrate a complex gene by environmental interaction affecting the OxPhos pathway.

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Senescence-associated changes in respiration and oxidative phosphorylation in primary human fibroblasts

Biochemical Journal ◽

10.1042/bj20040095 ◽

2004 ◽

Vol 380 (3) ◽

pp. 919-928 ◽

Cited By ~ 148

Author(s):

Eveline HUTTER ◽

Kathrin RENNER ◽

Gerald PFISTER ◽

Petra STÖCKL ◽

Pidder JANSEN-DÜRR ◽

...

Keyword(s):

Electron Transport ◽

Oxidative Phosphorylation ◽

Replicative Senescence ◽

Citrate Synthase ◽

Human Fibroblasts ◽

Respiratory Control ◽

Compensatory Mechanisms ◽

Intact Cells ◽

Atp Production ◽

Human Diploid Fibroblasts

Limitation of lifespan in replicative senescence is related to oxidative stress, which is probably both the cause and consequence of impaired mitochondrial respiratory function. The respiration of senescent human diploid fibroblasts was analysed by highresolution respirometry. To rule out cell-cycle effects, proliferating and growth-arrested young fibroblasts were used as controls. Uncoupled respiration, as normalized to citrate synthase activity, remained unchanged, reflecting a constant capacity of the respiratory chain. Oligomycin-inhibited respiration, however, was significantly increased in mitochondria of senescent cells, indicating a lower coupling of electron transport with phosphorylation. In contrast, growth-arrested young fibroblasts exhibited a higher coupling state compared with proliferating controls. In intact cells, partial uncoupling may lead to either decreased oxidative ATP production or a compensatory increase in routine respiration. To distinguish between these alternatives, we subtracted oligomycin-inhibited respiration from routine respiration, which allowed us to determine the part of respiratory activity coupled with ATP production. Despite substantial differences in the respiratory control ratio, ranging from 4 to 11 in the different experimental groups, a fixed proportion of respiratory capacity was maintained for coupled oxidative phosphorylation in all the experimental groups. This finding indicates that the senescent cells fully compensate for increased proton leakage by enhanced electron-transport activity in the routine state. These results provide a new insight into age-associated defects in mitochondrial function and compensatory mechanisms in intact cells.

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Protein kinase C-α inhibits the repair of oxidative phosphorylation after S-(1,2-dichlorovinyl)-l-cysteine injury in renal cells

AJP Renal Physiology ◽

10.1152/ajprenal.00216.2003 ◽

2004 ◽

Vol 287 (1) ◽

pp. F64-F73 ◽

Cited By ~ 18

Author(s):

Xiuli Liu ◽

Malinda L. Godwin ◽

Grażyna Nowak

Keyword(s):

Protein Kinase C ◽

Protein Kinase ◽

Oxidative Phosphorylation ◽

Atpase Activity ◽

Mitochondrial Function ◽

Recovery Period ◽

Β Subunit ◽

Atp Production ◽

Kinase C ◽

Mitochondrial Functions

Previously, we showed that physiological functions of renal proximal tubular cells (RPTC) do not recover following S-(1,2-dichlorovinyl)-l-cysteine (DCVC)-induced injury. This study investigated the role of protein kinase C-α (PKC-α) in the lack of repair of mitochondrial function in DCVC-injured RPTC. After DCVC exposure, basal oxygen consumption (Qo2), uncoupled Qo2, oligomycin-sensitive Qo2, F1F0-ATPase activity, and ATP production decreased, respectively, to 59, 27, 27, 57, and 68% of controls. None of these functions recovered. Mitochondrial transmembrane potential decreased 53% after DCVC injury but recovered on day 4. PKC-α was activated 4.3- and 2.5-fold on days 2 and 4, respectively, of the recovery period. Inhibition of PKC-α activation (10 nM Go6976) did not block DCVC-induced decreases in mitochondrial functions but promoted the recovery of uncoupled Qo2, oligomycin-sensitive Qo2, F1F0-ATPase activity, and ATP production. Protein levels of the catalytic β-subunit of F1F0-ATPase were not changed by DCVC or during the recovery period. Amino acid sequence analysis revealed that α-, β-, and ε-subunits of F1F0-ATPase have PKC consensus motifs. Recombinant PKC-α phosphorylated the β-subunit and decreased F1F0-ATPase activity in vitro. Serine but not threonine phosphorylation of the β-subunit was increased during late recovery following DCVC injury, and inhibition of PKC-α activation decreased this phosphorylation. We conclude that during RPTC recovery following DCVC injury, 1) PKC-α activation decreases F0F1-ATPase activity, oxidative phosphorylation, and ATP production; 2) PKC-α phosphorylates the β-subunit of F1F0-ATPase on serine residue; and 3) PKC-α does not mediate depolarization of RPTC mitochondria. This is the first report showing that PKC-α phosphorylates the catalytic subunit of F1F0-ATPase and that PKC-α plays an important role in regulating repair of mitochondrial function.

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Neuromuscular, cognitive and metabolic implications of McArdle Syndrome: a global overview

International Journal of Basic and Applied Sciences ◽

10.14419/ijbas.v4i4.5199 ◽

2015 ◽

Vol 4 (4) ◽

pp. 422

Author(s):

Lucas Vieira ◽

Rafaela Soares ◽

Stela Felipe ◽

Felipe Moura ◽

Christina Pacheco ◽

...

Keyword(s):

Oxidative Phosphorylation ◽

Nerve Conduction ◽

Motor Units ◽

Energy Sources ◽

Wind Effect ◽

Muscular Weakness ◽

Atp Production ◽

Exercise Induced ◽

Body Energy ◽

Low Rate

<p>Carbohydrates are the main source of body energy and they can be stored in the organism in form of glycogen and degraded when there is a need for energy. However, McArdle Syndrome patients exhibit problems to degrade glycogen due to a deficiency in myophosphorylase enzyme, making these patients intolerant to high intensity exercises because a lack of ATP available in muscle cells. It has been found muscular weakness and subsarcolemmal accumulation of glycogen in muscle fibers and in neuronal cells in McArdle Syndrome patients. In its later-onset form, it is associated to muscular dysmorphia, myoglobinuria and rhabdomyolisis. Analyzing the biochemical aspects, it is possible to notice that these patients have a low rate of ATP production due to a reduction in the availability of glucose, reducing oxidative phosphorylation. However, the metabolic “second wind” effect allows the use of other energy sources. Excessively decreased exercise-induced lactate is also characteristic of patients with McArdle Syndrome. Electromyography studies describe alterations in nerve conduction and the necessity of recruiting more motor units to contract muscle in these patients. McArdle Syndrome produces several metabolic changes in patients due to absence of myophophorylase activity. The practice of aerobic exercise acts positively in these patients probably by increasing mitochondrial metabolism.</p>

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Impaired Mitochondrial Fusion and Oxidative Phosphorylation Triggered by High Glucose Is Mediated by Tom22 in Endothelial Cells

Oxidative Medicine and Cellular Longevity ◽

10.1155/2019/4508762 ◽

2019 ◽

Vol 2019 ◽

pp. 1-23 ◽

Cited By ~ 1

Author(s):

Yi Zeng ◽

Qi Pan ◽

Xiaoxia Wang ◽

Dongxiao Li ◽

Yajun Lin ◽

...

Keyword(s):

Endothelial Cells ◽

Oxidative Phosphorylation ◽

Mitochondrial Dysfunction ◽

High Glucose ◽

Mitochondrial Dynamics ◽

Umbilical Vein ◽

Vascular Complications ◽

Mitochondrial Fusion ◽

Mitochondrial Outer Membrane ◽

Atp Production

Much evidence demonstrates that mitochondrial dysfunction plays a crucial role in the pathogenesis of vascular complications of diabetes. However, the signaling pathways through which hyperglycemia leads to mitochondrial dysfunction of endothelial cells are not fully understood. Here, we treated human umbilical vein endothelial cells (HUVECs) with high glucose and examined the role of translocase of mitochondrial outer membrane (Tom) 22 on mitochondrial dynamics and cellular function. Impaired Tom22 expression and protein expression of oxidative phosphorylation (OXPHOS) as well as decreased mitochondrial fusion were observed in HUVECs treated with high glucose. The deletion of Tom22 resulted in reduced mitochondrial fusion and ATP production and increased apoptosis in HUVECs. The overexpression of Tom22 restored the balance of mitochondrial dynamics and OXPHOS disrupted by high glucose. Importantly, we found that Tom22 modulates mitochondrial dynamics and OXPHOS by interacting with mitofusin (Mfn) 1. Taken together, our findings demonstrate for the first time that Tom22 is a novel regulator of both mitochondrial dynamics and bioenergetic function and contributes to cell survival following high-glucose exposure.

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