Secondary abnormalities of mitochondrial DNA associated with neurodegeneration

1999 ◽  
Vol 66 ◽  
pp. 99-110 ◽  
Author(s):  
S.J. Tabrizi ◽  
A.H.V. Schapira
Keyword(s):  
Skeletal Muscle ◽  
Mitochondrial Dna ◽  
Complex I ◽  
Tricarboxylic Acid Cycle ◽  
Energy Requirement ◽  
Mitochondrial Protein ◽  
High Energy ◽  
Resonance Spectroscopy ◽  
Mtdna Mutation ◽  
Mitochondrial Iron

The central nervous system has a particularly high energy requirement, thus making it very susceptible to defects in mitochondrial function. A number of neurodegenerative diseases, in particular Parkinson's disease (PD), Huntington's disease (HD) and Friedreich's ataxia (FRDA), are associated with mitochondrial dysfunction. The identification of a mitochondrial complex-I defect in PD provides a link between toxin models of the disease, and clues to the pathogenesis of idiopathic PD. We have undertaken genomic transplantation studies involving the transfer of mitochondrial DNA (mtDNA) from PD patients with a complex-I defect to a novel nuclear background. Histochemical, immunohistochemical and functional analysis of the resulting cybrids all showed a pattern in the PD clones indicative of a mtDNA mutation. There is good evidence for the involvement of defective energy metabolism and excitotoxicity in the aetiology of HD. We, and others, have shown a severe deficiency of complex II/III confined to the striatum that mimics the toxin-induced animal models of HD. There is also a milder defect in complex IV in the caudate. The tricarboxylic acid cycle enzyme aconitase is particularly sensitive to inhibition by peroxynitrite and superoxide radicals. We have found this enzyme to be severely decreased in HD caudate, putamen and cortex in a pattern that parallels the severity of neuronal loss seen. We propose a scheme for the role of nitric oxide, free radicals and excitotoxicity in the pathogenesis of HD. FRDA is caused by an expanded GAA repeat in intron 1 of the X25 gene encoding a protein called frataxin. Frataxin is widely expressed and is a mitochondrial protein, although its function is unknown. We have found abnormal magnetic resonance spectroscopy in the skeletal muscle of FRDA patients, which parallels our biochemical findings of reduced complexes I-III in patients' heart and skeletal muscle. There is also reduced aconitase activity in these areas. Increased iron deposition was seen in patients' tissues in a pattern consistent with a mitochondrial location. The mitochondrial iron accumulation, defective respiratory chain activity and aconitase dysfunction suggest that frataxin may be involved in mitochondrial iron regulation. There is also evidence that oxidative stress contributes to cellular toxicity.

Differential energetic response of brain vs. skeletal muscle upon glycemic variations in healthy humans

2008 ◽  
Vol 294 (1) ◽  
pp. R12-R16 ◽  
Author(s):  
Kerstin M. Oltmanns ◽  
Uwe H. Melchert ◽  
Harald G. Scholand-Engler ◽  
Maria C. Howitz ◽  
Bernd Schultes ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Underlying Mechanism ◽  
High Energy ◽  
Resonance Spectroscopy ◽  
Energy Status ◽  
High Energy Phosphate ◽  
Available Energy ◽  
Healthy Humans ◽  
High Energy Phosphate Metabolism ◽  
The Brain

The brain regulates all metabolic processes within the organism, and therefore, its energy supply is preserved even during fasting. However, the underlying mechanism is unknown. Here, it is shown, using 31P-magnetic resonance spectroscopy that during short periods of hypoglycemia and hyperglycemia, the brain can rapidly increase its high-energy phosphate content, whereas there is no change in skeletal muscle. We investigated the key metabolites of high-energy phosphate metabolism as rapidly available energy stores by 31P MRS in brain and skeletal muscle of 17 healthy men. Measurements were performed at baseline and during dextrose or insulin-induced hyperglycemia and hypoglycemia. During hyperglycemia, phosphocreatine (PCr) concentrations increased significantly in the brain ( P = 0.013), while there was a similar trend in the hypopglycemic condition ( P = 0.055). Skeletal muscle content remained constant in both conditions ( P > 0.1). ANOVA analyses comparing changes from baseline to the respective glycemic plateau in brain (up to +15%) vs. muscle (up to −4%) revealed clear divergent effects in both conditions ( P < 0.05). These effects were reflected by PCr/Pi ratio ( P < 0.05). Total ATP concentrations revealed the observed divergency only during hyperglycemia ( P = 0.018). These data suggest that the brain, in contrast to peripheral organs, can activate some specific mechanisms to modulate its energy status during variations in glucose supply. A disturbance of these mechanisms may have far-reaching implications for metabolic dysregulation associated with obesity or diabetes mellitus.

Interrelationship of oxidative metabolism and local perfusion demonstrated by NMR in human skeletal muscle

1996 ◽  
Vol 81 (5) ◽  
pp. 2221-2228 ◽  
Author(s):  
Jean-François Toussaint ◽  
Kenneth K. Kwong ◽  
Fidelis M’Kparu ◽  
Robert M. Weisskoff ◽  
Paul J. Laraia ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Magnetic Resonance ◽  
Time Constant ◽  
Oxidative Metabolism ◽  
Human Skeletal Muscle ◽  
Plantar Flexion ◽  
High Energy ◽  
Resonance Spectroscopy ◽  
Mean Flow ◽  
Normal Volunteers

Toussaint, Jean-François, Kenneth K. Kwong, Fidelis M’Kparu, Robert M. Weisskoff, Paul J. LaRaia, and Howard L. Kantor.Interrelationship of oxidative metabolism and local perfusion demonstrated by NMR in human skeletal muscle. J. Appl. Physiol. 81(5): 2221–2228, 1996.—Using nuclear magnetic resonance (NMR), we have examined the relationship of high-energy phosphate metabolism and perfusion in human soleus and gastrocnemius muscles. With31P-NMR spectroscopy, we monitored phosphocreatine (PCr) decay and recovery in eight normal volunteers and four heart failure patients performing ischemic plantar flexion. By using echo-planar imaging, perfusion was independently measured by a local [inversion-recovery (T1-flow)] and a regional technique (NMR-plethysmography). After correction for its pH dependence, PCr recovery time constant is 27.5 ± 8.0 s in normal volunteers, with mean flow 118 ± 75 (soleus and gastrocnemius T1-flow) and 30.2 ± 9.7 ml ⋅ 100 ml−1 ⋅ min−1(NMR-plethysmography-flow). We demonstrate a positive correlation between PCr time constant and local perfusion given by y = 50 − 0.15 x( r 2 = 0.68, P = 0.01) for the 8 normal subjects, and y = 64 − 0.24 x( r 2 = 0.83, P = 0.0001) for the 12 subjects recruited in the study. Regional perfusion techniques also show a significant but weaker correlation. Using this totally noninvasive method, we conclude that aerobic ATP resynthesis is related to the magnitude of perfusion, i.e., O2availability, and demonstrate that magnetic resonance imaging and magnetic resonance spectroscopy together can accurately assess muscle functional status.

scholarly journals Sexual dimorphism in human skeletal muscle mitochondrial bioenergetics in response to type 1 diabetes

2020 ◽  
Vol 318 (1) ◽  
pp. E44-E51 ◽  
Author(s):  
Cynthia M. F. Monaco ◽  
Catherine A. Bellissimo ◽  
Meghan C. Hughes ◽  
Sofhia V. Ramos ◽  
Robert Laham ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Type 1 Diabetes ◽  
Sexual Dimorphism ◽  
Respiratory Function ◽  
Complex I ◽  
Mitochondrial Protein ◽  
Mitochondrial Bioenergetics ◽  
The Impact ◽  
Mitochondrial Respiratory

Sexual dimorphism in mitochondrial respiratory function has been reported in young women and men without diabetes, which may have important implications for exercise. The purpose of this study was to determine if sexual dimorphism exists in skeletal muscle mitochondrial bioenergetics in people with type 1 diabetes (T1D). A resting muscle microbiopsy was obtained from women and men with T1D ( n = 10/8, respectively) and without T1D (control; n = 8/7, respectively). High-resolution respirometry and spectrofluorometry were used to measure mitochondrial respiratory function, hydrogen peroxide (mH2O2) emission and calcium retention capacity (mCRC) in permeabilized myofiber bundles. The impact of T1D on mitochondrial bioenergetics between sexes was interrogated by comparing the change between women and men with T1D relative to the average values of their respective sex-matched controls (i.e., delta). These aforementioned analyses revealed that men with T1D have increased skeletal muscle mitochondrial complex I sensitivity but reduced complex II sensitivity and capacity in comparison to women with T1D. mH2O2 emission was lower in women compared with men with T1D at the level of complex I (succinate driven), whereas mCRC and mitochondrial protein content remained similar between sexes. In conclusion, women and men with T1D exhibit differential responses in skeletal muscle mitochondrial bioenergetics. Although larger cohort studies are certainly required, these early findings nonetheless highlight the importance of considering sex as a variable in the care and treatment of people with T1D (e.g., benefits of different exercise prescriptions).

scholarly journals Efficient selection and characterization of mutants of a human cell line which are defective in mitochondrial DNA-encoded subunits of respiratory NADH dehydrogenase.

1995 ◽  
Vol 15 (2) ◽  
pp. 964-974 ◽  
Author(s):  
G Hofhaus ◽  
G Attardi
Keyword(s):  
Mitochondrial Dna ◽  
Cell Line ◽  
Human Cell ◽  
Complex I ◽  
Mammalian Cells ◽  
Nadh Dehydrogenase ◽  
Frameshift Mutation ◽  
Human Cell Line ◽  
Mtdna Mutation ◽  
Selection Scheme

The mitochondrial NADH dehydrogenase (complex I) in mammalian cells is a multimeric enzyme consisting of approximately 40 subunits, 7 of which are encoded in mitochondrial DNA (mtDNA). Very little is known about the function of these mtDNA-encoded subunits. In this paper, we describe the efficient isolation from a human cell line of mutants affected in any of these subunits. In the course of analysis of eight mutants of the human cell line VA2B selected for their resistance to high concentrations of the complex I inhibitor rotenone, seven were found to be respiration deficient, and among these, six exhibited a specific defect of complex I. Transfer of mitochondria from these six mutants into human mtDNA-less cells revealed, surprisingly, in all cases a cotransfer of the complex I defect but not of the rotenone resistance. This result indicated that the rotenone resistance resulted from a nuclear mutation, while the respiration defect was produced by an mtDNA mutation. A detailed molecular analysis of the six complex I-deficient mutants revealed that two of them exhibited a frameshift mutation in the ND4 gene, in homoplasmic or in heteroplasmic form, resulting in the complete or partial loss, respectively, of the ND4 subunit; two other mutants exhibited a frameshift mutation in the ND5 gene, in near-homoplasmic or heteroplasmic form, resulting in the ND5 subunit being undetectable or strongly decreased, respectively. It was previously reported (G. Hofhaus and G. Attardi, EMBO J. 12:3043-3048, 1993) that the mutant completely lacking the ND4 subunit exhibited a total loss of NADH:Q1 oxidoreductase activity and a lack of assembly of the mtDNA-encoded subunits of complex I. By contrast, in the mutant characterized in this study in which the ND5 subunit was not detectable and which was nearly totally deficient in complex I activity, the capacity to assemble the mtDNA-encoded subunits of the enzyme was preserved, although with a decreased efficiency or a reduced stability of the assembled complex. The two remaining complex I-deficient mutants exhibited a normal rate of synthesis and assembly of the mtDNA-encoded subunits of the enzyme, and the mtDNA mutation(s) responsible for their NADH dehydrogenase defect remains to be identified. The selection scheme used in this work has proven to be very valuable for the isolation of mutants from the VA2B cell line which are affected in different mtDNA-encoded subunits of complex I and may be applicable to other cell lines.

Human muscle fatigue after glycogen depletion: a 31P magnetic resonance study

1992 ◽  
Vol 73 (1) ◽  
pp. 75-81 ◽  
Author(s):  
L. A. Bertocci ◽  
J. L. Fleckenstein ◽  
J. Antonio
Keyword(s):  
Skeletal Muscle ◽  
Magnetic Resonance ◽  
Muscle Fatigue ◽  
High Energy ◽  
Resonance Spectroscopy ◽  
High Energy Phosphates ◽  
Handgrip Exercise ◽  
Glycogen Depletion ◽  
Skeletal Muscle Fatigue ◽  
Exercise Induced

To differentiate the effects of high energy phosphates, pH, and [H2PO4-] on skeletal muscle fatigue, intracellular acidosis during handgrip exercise was attenuated by prolonged submaximal exercise. Healthy human subjects (n = 6) performed 5-min bouts of maximal rhythmic handgrip (RHG) before (CONTROL) and after prolonged (60-min) handgrip exercise (ATTEN-EX) designed to attenuate lactic acidosis in active muscle by partially depleting muscle glycogen. Concentrations of free intracellular phosphocreatine ([PCr]), adenosine triphosphate ([ATP]), and orthophosphate ([P(i)]) and pH were measured by 31P nuclear magnetic resonance spectroscopy and used to calculate adenosine diphosphate [ADP], [H2PO4-], and [HPO4(2-)]. Handgrip force output was measured with a dynamometer, and fatigue was determined by loss of maximal contractile force. After ATTEN-EX, the normal exercise-induced muscle acidosis was reduced. At peak CONTROL RHG, pH fell to 6.3 +/- 0.1 (SE) and muscle fatigue was correlated with [PCr] (r = 0.83), [P(i)] (r = 0.82), and [H2PO4-] (r = 0.81); [ADP] was 22.0 +/- 5.7 mumol/kg. At peak RHG after ATTEN-EX, pH was 6.9 +/- 0.1 and [ADP] was 116.1 +/- 18.2 mumol/kg, although [PCr] and [P(i)] were not different from CONTROL RHG (P greater than 0.05). After ATTEN-EX, fatigue correlated most closely with [ADP] (r = 0.84). The data indicate that skeletal muscle fatigue 1) is multifactorial, 2) can occur without decreased pH or increased [H2PO4-], and 3) is correlated with [ADP] after exercise-induced glycogen depletion.

scholarly journals Enhanced Skeletal Muscle Oxidative Capacity and Capillary-to-Fiber Ratio Following Moderately Increased Testosterone Exposure in Young Healthy Women

2020 ◽  
Vol 11 ◽  
Author(s):  
Daniele A. Cardinale ◽  
Oscar Horwath ◽  
Jona Elings-Knutsson ◽  
Torbjörn Helge ◽  
Manne Godhe ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Complex I ◽  
Citrate Synthase ◽  
Mitochondrial Protein ◽  
Capillary Density ◽  
Oxidative Capacity ◽  
System Capacity ◽  
Endurance Capacity ◽  
Muscle Oxidative Capacity ◽  
Before And After

Background: Recently, it was shown that exogenously administered testosterone enhances endurance capacity in women. In this study, our understanding on the effects of exogenous testosterone on key determinants of oxygen transport and utilization in skeletal muscle is expanded.Methods: In a double-blinded, randomized, placebo-controlled trial, 48 healthy active women were randomized to 10 weeks of daily application of 10 mg of testosterone cream or placebo. Before and after the intervention, VO2 max, body composition, total hemoglobin (Hb) mass and blood volumes were assessed. Biopsies from the vastus lateralis muscle were obtained before and after the intervention to assess mitochondrial protein abundance, capillary density, capillary-to-fiber (C/F) ratio, and skeletal muscle oxidative capacity.Results: Maximal oxygen consumption per muscle mass, Hb mass, blood, plasma and red blood cell volumes, capillary density, and the abundance of mitochondrial protein levels (i.e., citrate synthase, complexes I, II, III, IV-subunit 2, IV-subunit 4, and V) were unchanged by the intervention. However, the C/F ratio, specific mitochondrial respiratory flux activating complex I and linked complex I and II, uncoupled respiration and electron transport system capacity, but not leak respiration or fat respiration, were significantly increased following testosterone administration compared to placebo.Conclusion: This study provides novel insights into physiological actions of increased testosterone exposure on key determinants of oxygen diffusion and utilization in skeletal muscle of women. Our findings show that higher skeletal muscle oxidative capacity coupled to higher C/F ratio could be major contributing factors that improve endurance performance following moderately increased testosterone exposure.

scholarly journals Linking bioenergetic function of mitochondria to tissue-specific molecular fingerprints

2019 ◽  
Vol 317 (2) ◽  
pp. E374-E387 ◽  
Author(s):  
Lisa Kappler ◽  
Miriam Hoene ◽  
Chunxiu Hu ◽  
Christine von Toerne ◽  
Jia Li ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Mitochondrial Function ◽  
Complex I ◽  
Mitochondrial Protein ◽  
Liver Mitochondria ◽  
Quinone Oxidoreductase ◽  
Molecular Fingerprints ◽  
Consistent Finding ◽  
Tissue Specific ◽  
Muscle Mitochondria

Mitochondria are dynamic organelles with diverse functions in tissues such as liver and skeletal muscle. To unravel the mitochondrial contribution to tissue-specific physiology, we performed a systematic comparison of the mitochondrial proteome and lipidome of mice and assessed the consequences hereof for respiration. Liver and skeletal muscle mitochondrial protein composition was studied by data-independent ultra-high-performance (UHP)LC-MS/MS-proteomics, and lipid profiles were compared by UHPLC-MS/MS lipidomics. Mitochondrial function was investigated by high-resolution respirometry in samples from mice and humans. Enzymes of pyruvate oxidation as well as several subunits of complex I, III, and ATP synthase were more abundant in muscle mitochondria. Muscle mitochondria were enriched in cardiolipins associated with higher oxidative phosphorylation capacity and flexibility, in particular CL(18:2)4 and 22:6-containing cardiolipins. In contrast, protein equipment of liver mitochondria indicated a shuttling of complex I substrates toward gluconeogenesis and ketogenesis and a higher preference for electron transfer via the flavoprotein quinone oxidoreductase pathway. Concordantly, muscle and liver mitochondria showed distinct respiratory substrate preferences. Muscle respired significantly more on the complex I substrates pyruvate and glutamate, whereas in liver maximal respiration was supported by complex II substrate succinate. This was a consistent finding in mouse liver and skeletal muscle mitochondria and human samples. Muscle mitochondria are tailored to produce ATP with a high capacity for complex I-linked substrates. Liver mitochondria are more connected to biosynthetic pathways, preferring fatty acids and succinate for oxidation. The physiologic diversity of mitochondria may help to understand tissue-specific disease pathologies and to develop therapies targeting mitochondrial function.

Progressive decrease of intramyocellular accumulation of H+ and Pi in human skeletal muscle during repeated isotonic exercise

2003 ◽  
Vol 284 (6) ◽  
pp. C1490-C1496 ◽  
Author(s):  
J. Rico-Sanz
Keyword(s):  
Skeletal Muscle ◽  
Perceived Exertion ◽  
Plantar Flexion ◽  
High Energy ◽  
Rating Of Perceived Exertion ◽  
Resonance Spectroscopy ◽  
High Energy Phosphates ◽  
Hydrogen Ions ◽  
Isotonic Exercise ◽  
Wet Weight

The purpose of this study was to evaluate the hypotheses that accumulation of hydrogen ions and/or inorganic phosphate (Pi) in skeletal muscle increases with repeated bouts of isotonic exercise. 31P-Magnetic resonance spectroscopy was used to examine the gastrocnemius muscle of seven highly aerobically trained females during four bouts of isotonic plantar flexion. The exercise bouts ( EX1- 4) of 3 min and 18 s were separated by 3 min and 54 s of complete rest. Muscle ATP did not change during the four bouts. Phosphocreatine (PCr) degradation during EX1 (13.3 ± 2.4 mmol/kg wet weight) was higher ( P < 0.01) compared with EX3- 4(9.7 ± 1.6 and 9.6 ± 1.8 mmol/kg wet weight, respectively). The intramyocellular pH at the end of EX1 (6.87 ± 0.05) was significantly lower ( P < 0.001) than those of EX2 (6.97 ± 0.02), EX3 (7.02 ± 0.01), and EX4 (7.02 ± 0.02). Total Pi and diprotonated Pi were significantly higher ( P < 0.001) at the end of EX1 (17.3 ± 2.7 and 7.8 ± 1.6 mmol/kg wet weight, respectively) compared with the values at the end of EX3 and EX4. The monoprotonated Pi at the end of EX1 (9.5 ± 1.2 mmol/kg wet weight) was also significantly higher ( P < 0.001) than that after EX4 (7.5 ± 1.1 mmol/kg wet weight). Subjects' rating of perceived exertion increased ( P < 0.001) toward exhaustion as the number of exercises progressed (7.1 ± 0.4, EX1; 8.0 ± 0.3, EX2; 8.5 ± 0.3, EX3; and 9.0 ± 0.4, EX4; scale from 0 to 10). The present results indicate that human muscle fatigue during repeated intense isotonic exercise is not due to progressive depletion of high energy phosphates nor to intracellular accumulation of hydrogen ions, total, mono-, or diprotonated Pi.

scholarly journals Skeletal Muscle Mitochondrial Adaptations to Maximal Strength Training in Older Adults

2020 ◽  
Vol 75 (12) ◽  
pp. 2269-2277
Author(s):  
Ole Kristian Berg ◽  
Oh Sung Kwon ◽  
Thomas J Hureau ◽  
Heather L Clifton ◽  
Taylor S Thurston ◽  
...  
Keyword(s):  
Older Adults ◽  
Skeletal Muscle ◽  
Strength Training ◽  
Complex I ◽  
Production Efficiency ◽  
Citrate Synthase ◽  
Resonance Spectroscopy ◽  
Maximal Strength ◽  
Mitochondrial Adaptations

Abstract Maximal strength training (MST) results in robust improvements in skeletal muscle force production, efficiency, and mass. However, the effects of MST on muscle mitochondria are still unknown. Accordingly, the purpose of this study was to examine, from the molecular level to whole-muscle, mitochondrial adaptations induced by 8 weeks of knee-extension MST in the quadriceps of 10 older adults using immunoblotting, spectrophotometry, high-resolution respirometry in permeabilized muscle fibers, in vivo 31P magnetic resonance spectroscopy (31P-MRS), and gas exchange. As anticipated, MST resulted in an increased isometric knee-extensor force from 133 ± 36 to 147 ± 49 Nm (p &lt; .05) and quadriceps muscle volume from 1,410 ± 103 to 1,555 ± 455 cm3 (p &lt; .05). Mitochondrial complex (I–V) protein abundance and citrate synthase activity were not significantly altered by MST. Assessed ex vivo, maximal ADP-stimulated respiration (state 3CI+CII, PRE: 23 ± 6 and POST: 14 ± 5 ρM·mg−1·s−1, p &lt; .05), was decreased by MST, predominantly, as a result of a decline in complex I-linked respiration (p &lt; .05). Additionally, state 3 free-fatty acid linked respiration was decreased following MST (PRE: 19 ± 5 and POST: 14 ± 3 ρM·mg−1·s−1, p &lt; .05). Assessed in vivo, MST slowed the PCr recovery time constant (PRE: 49 ± 13 and POST: 57 ± 16 seconds, p &lt; .05) and lowered, by ~20% (p = .055), the quadriceps peak rate of oxidative ATP synthesis, but did not significantly alter the oxidation of lipid. Although these, likely qualitative, mitochondrial adaptations are potentially negative in terms of skeletal muscle energetic capacity, they need to be considered in light of the many improvements in muscle function that MST affords older adults.

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