In this study, we report on a novel heteroplasmic pathogenic variant in mitochondrial DNA (mtDNA). The studied patient had myoclonus, epilepsy, muscle weakness, and hearing impairment and harbored a heteroplasmic m.8315A>C variant in the MTTK gene with a mutation load ranging from 71% to >96% in tested tissues. In muscle mitochondria, markedly decreased activities of respiratory chain complex I + III and complex IV were observed together with mildly reduced amounts of complex I and complex V (with the detection of V*- and free F1-subcomplexes) and a diminished level of complex IV holoenzyme. This pattern was previously seen in other MTTK pathogenic variants. The novel variant was not present in internal and publicly available control databases. Our report further expands the spectrum of MTTK variants associated with mitochondrial encephalopathies in adults.

• MeSH
• dospělí MeSH
• lidé MeSH
• mitochondriální DNA genetika   MeSH
• mitochondriální encefalomyopatie * patologie   MeSH
• respirační komplex IV MeSH
• svalové mitochondrie metabolismus   MeSH
• syndrom MERRF * genetika   patologie   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Mitochondria are considered central regulator of the aging process; however, majority of studies dealing with the impact of age on mitochondrial oxygen consumption focused on skeletal muscle concluding (although not uniformly) a general declining trend with advancing age. In addition, gender related differences in mitochondrial respiration have not been satisfactorily described yet. The aim of the present study was to evaluate mitochondrial oxygen consumption in various organs of aging male and female Fischer 344 rats at the ages of 6, 12 and 24 months. Mitochondrial respiration of homogenized (skeletal muscle, left and right heart ventricle, hippocampus, cerebellum, kidney cortex), gently mechanically permeabilized (liver) tissue or intact cells (platelets) was determined using high-resolution respirometry (oxygraphs O2k, Oroboros, Austria). The pattern of age-related changes differed in each tissue: in the skeletal muscle and kidney cortex of both sexes and in female heart, parameters of mitochondrial respiration significantly declined with age. Resting respiration of intact platelets displayed an increasing trend and it did not correlate with skeletal muscle respiratory states. In the heart of male rats and brain tissues of both sexes, respiratory states remained relatively stable over analyzed age categories with few exceptions of lower mitochondrial oxygen consumption at the age of 24 months. In the liver, OXPHOS capacity was higher in females than in males with either no difference between the ages of 6 and 24 months or even significant increase at the age of 24 months in the male rats. In conclusion, the results of our study indicate that the concept of general pattern of age-dependent decline in mitochondrial oxygen consumption across different organs and tissues could be misleading. Also, the statement of higher mitochondrial respiration in females seems to be conflicting, since the gender-related differences may vary with the tissue studied, combination of substrates used and might be better detectable at younger ages than in old animals.

• MeSH
• anestezie MeSH
• buněčné dýchání MeSH
• dýchání MeSH
• kosterní svaly metabolismus   MeSH
• krysa rodu rattus MeSH
• mitochondrie * MeSH
• spotřeba kyslíku fyziologie   MeSH
• stárnutí MeSH
• svalové mitochondrie * metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Rheumatoid arthritis (RA) and its animal model adjuvant arthritis (AA) are inflammatory diseases characterized by chronic inflammation, systemic oxidative stress and disturbed mitochondrial bioenergetics of skeletal muscle. The present study aimed to evaluate the effects of coenzyme Q10 - CoQ10 (100 mg/kg b.w.), omega-3-polyunsaturated fatty acids - omega-3-PUFA (400 mg/kg b.w.) and their combined treatment in AA on impaired skeletal muscle mitochondrial bioenergetics, inflammation and changes in levels CoQ9 and CoQ10 in plasma. Markers of inflammation (C-reactive protein, monocyte-chemotactic protein-1), antioxidant capacity of plasma, respiratory chain parameters of skeletal muscle mitochondria and concentrations of CoQ9 and CoQ10 in plasma and in muscle tissue were estimated. Treatment of the arthritic rats with CoQ10, omega-3-PUFA alone and in combination partially reduced markers of inflammation and increased antioxidant capacity of plasma, significantly increased concentrations of coenzyme Q in mitochondria and improved mitochondrial function in the skeletal muscle. Combined treatment has similar effect on the mitochondrial function as monotherapies; however, it has affected inflammation and antioxidant status more intensively than monotherapies. Long-term supplementary administration of coenzyme Q10 and omega-3-PUFA and especially their combination is able to restore the impaired mitochondrial bioenergetics and antioxidant status in AA.

• MeSH
• antioxidancia metabolismus   MeSH
• artritida experimentální krev   dietoterapie   MeSH
• C-reaktivní protein metabolismus   MeSH
• chemokin CCL2 krev   MeSH
• kyseliny mastné omega-3 terapeutické užití   MeSH
• potkani inbrední LEW MeSH
• potravní doplňky MeSH
• revmatoidní artritida krev   dietoterapie   MeSH
• svalové mitochondrie metabolismus   MeSH
• ubichinon analogy a deriváty   metabolismus   terapeutické užití   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• hodnotící studie MeSH

INTRODUCTION: Propofol causes a profound inhibition of fatty acid oxidation and reduces spare electron transfer chain capacity in a range of human and rodent cells and tissues-a feature that might be related to the pathogenesis of Propofol Infusion Syndrome. We aimed to explore the mechanism of propofol-induced alteration of bioenergetic pathways by describing its kinetic characteristics. METHODS: We obtained samples of skeletal and cardiac muscle from Wistar rat (n = 3) and human subjects: vastus lateralis from hip surgery patients (n = 11) and myocardium from brain-dead organ donors (n = 10). We assessed mitochondrial functional indices using standard SUIT protocol and high resolution respirometry in fresh tissue homogenates with or without short-term exposure to a range of propofol concentration (2.5-100 μg/ml). After finding concentrations of propofol causing partial inhibition of a particular pathways, we used that concentration to construct kinetic curves by plotting oxygen flux against substrate concentration during its stepwise titration in the presence or absence of propofol. By spectrophotometry we also measured the influence of the same propofol concentrations on the activity of isolated respiratory complexes. RESULTS: We found that human muscle and cardiac tissues are more sensitive to propofol-mediated inhibition of bioenergetic pathways than rat's tissue. In human homogenates, palmitoyl carnitine-driven respiration was inhibited at much lower concentrations of propofol than that required for a reduction of electron transfer chain capacity, suggesting FAO inhibition mechanism different from downstream limitation or carnitine-palmitoyl transferase-1 inhibition. Inhibition of Complex I was characterised by more marked reduction of Vmax, in keeping with non-competitive nature of the inhibition and the pattern was similar to the inhibition of Complex II or electron transfer chain capacity. There was neither inhibition of Complex IV nor increased leak through inner mitochondrial membrane with up to 100 μg/ml of propofol. If measured in isolation by spectrophotometry, propofol 10 μg/ml did not affect the activity of any respiratory complexes. CONCLUSION: In human skeletal and heart muscle homogenates, propofol in concentrations that are achieved in propofol-anaesthetized patients, causes a direct inhibition of fatty acid oxidation, in addition to inhibiting flux of electrons through inner mitochondrial membrane. The inhibition is more marked in human as compared to rodent tissues.

• MeSH
• druhová specificita MeSH
• krysa rodu rattus MeSH
• lidé středního věku MeSH
• lidé MeSH
• mastné kyseliny metabolismus   MeSH
• oxidace-redukce účinky léků   MeSH
• potkani Wistar MeSH
• propofol farmakologie   MeSH
• respirační komplex I metabolismus   MeSH
• respirační komplex IV metabolismus   MeSH
• senioři MeSH
• srdeční mitochondrie metabolismus   MeSH
• svalové mitochondrie metabolismus   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Skeletal muscle wasting and atrophy is one of the more severe clinical impairments resulting from the progression of Huntington's disease (HD). Mitochondrial dysfunction may play a significant role in the etiology of HD, but the specific condition of mitochondria in muscle has not been widely studied during the development of HD. To determine the role of mitochondria in skeletal muscle during the early stages of HD, we analyzed quadriceps femoris muscle from 24-, 36-, 48- and 66-month-old transgenic minipigs that expressed the N-terminal portion of mutated human huntingtin protein (TgHD) and age-matched wild-type (WT) siblings. We found altered ultrastructure of TgHD muscle tissue and mitochondria. There was also significant reduction of activity of citrate synthase and respiratory chain complexes (RCCs) I, II and IV, decreased quantity of oligomycin-sensitivity conferring protein (OSCP) and the E2 subunit of pyruvate dehydrogenase (PDHE2), and differential expression of optic atrophy 1 protein (OPA1) and dynamin-related protein 1 (DRP1) in the skeletal muscle of TgHD minipigs. Statistical analysis identified several parameters that were dependent only on HD status and could therefore be used as potential biomarkers of disease progression. In particular, the reduction of biomarker RCCII subunit SDH30 quantity suggests that similar pathogenic mechanisms underlie disease progression in TgHD minipigs and HD patients. The perturbed biochemical phenotype was detectable in TgHD minipigs prior to the development of ultrastructural changes and locomotor impairment, which become evident at the age of 48 months. Mitochondrial disturbances may contribute to energetic depression in skeletal muscle in HD, which is in concordance with the mobility problems observed in this model.This article has an associated First Person interview with the first author of the paper.

• MeSH
• DNA metabolismus   MeSH
• energetický metabolismus * MeSH
• geneticky modifikovaná zvířata MeSH
• Huntingtonova nemoc metabolismus   patologie   MeSH
• kosterní svaly metabolismus   ultrastruktura   MeSH
• lidé MeSH
• miniaturní prasata MeSH
• mitochondriální proteiny metabolismus   MeSH
• modely nemocí na zvířatech * MeSH
• mutace MeSH
• oxidativní fosforylace MeSH
• prasata MeSH
• progrese nemoci MeSH
• protein huntingtin genetika   MeSH
• svalové mitochondrie metabolismus   ultrastruktura   MeSH
• tělesná hmotnost MeSH
• transport elektronů MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

OBJECTIVES: Propofol may adversely affect the function of mitochondria and the clinical features of propofol infusion syndrome suggest that this may be linked to propofol-related bioenergetic failure. We aimed to assess the effect of therapeutic propofol concentrations on energy metabolism in human skeletal muscle cells. DESIGN: In vitro study on human skeletal muscle cells. SETTINGS: University research laboratories. SUBJECTS: Patients undergoing hip surgery and healthy volunteers. INTERVENTIONS: Vastus lateralis biopsies were processed to obtain cultured myotubes, which were exposed to a range of 1-10 μg/mL propofol for 96 hours. MEASUREMENTS AND MAIN RESULTS: Extracellular flux analysis was used to measure global mitochondrial functional indices, glycolysis, fatty acid oxidation, and the functional capacities of individual complexes of electron transfer chain. In addition, we used [1-C]palmitate to measure fatty acid oxidation and spectrophotometry to assess activities of individual electron transfer chain complexes II-IV. Although cell survival and basal oxygen consumption rate were only affected by 10 μg/mL of propofol, concentrations as low as 1 μg/mL reduced spare electron transfer chain capacity. Uncoupling effects of propofol were mild, and not dependent on concentration. There was no inhibition of any respiratory complexes with low dose propofol, but we found a profound inhibition of fatty acid oxidation. Addition of extra fatty acids into the media counteracted the propofol effects on electron transfer chain, suggesting inhibition of fatty acid oxidation as the causative mechanism of reduced spare electron transfer chain capacity. Whether these metabolic in vitro changes are observable in other organs and at the whole-body level remains to be investigated. CONCLUSIONS: Concentrations of propofol seen in plasma of sedated patients in ICU cause a significant inhibition of fatty acid oxidation in human skeletal muscle cells and reduce spare capacity of electron transfer chain in mitochondria.

• MeSH
• energetický metabolismus MeSH
• hypnotika a sedativa škodlivé účinky   farmakologie   MeSH
• kosterní svalová vlákna účinky léků   metabolismus   MeSH
• kosterní svaly cytologie   účinky léků   metabolismus   MeSH
• kultivované buňky MeSH
• lidé MeSH
• propofol škodlivé účinky   farmakologie   MeSH
• senioři MeSH
• spotřeba kyslíku účinky léků   MeSH
• svalové mitochondrie účinky léků   metabolismus   MeSH
• techniky in vitro MeSH
• Check Tag
• lidé MeSH
• senioři MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

• MeSH
• diabetes mellitus 1. typu patofyziologie   MeSH
• kosterní svaly * patologie   ultrastruktura   MeSH
• lidé MeSH
• mitochondriální myopatie etiologie   patologie   MeSH
• mladý dospělý MeSH
• svalové mitochondrie metabolismus   ultrastruktura   MeSH
• Check Tag
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• Publikační typ
• novinové články MeSH

The aging process is associated with a decline in mitochondrial functions. Mitochondria dysfunction is involved in initiation and progression of many health problems including neuromuscular, metabolic and cardiovascular diseases. It is well known that endurance exercise improves mitochondrial function, especially in the elderly. However, recent studies have demonstrated that resistance training lead also to substantial increases in mitochondrial function in skeletal muscle. A comprehensive understanding of the cellular mechanisms involved in the skeletal muscle mitochondrial adaptations to exercise training in healthy elderly subjects, can help practitioners to design and prescribe more effective exercise trainings.

• MeSH
• cvičení fyziologie   MeSH
• fyzická vytrvalost fyziologie   MeSH
• fyziologická adaptace fyziologie   MeSH
• kosterní svaly metabolismus   MeSH
• lidé MeSH
• PPARGC1A metabolismus   MeSH
• stárnutí metabolismus   MeSH
• svalové mitochondrie metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

BACKGROUND: The lipophilic positively charged moiety of triphenylphosphonium (TPP+) has been used to target a range of biologically active compounds including antioxidants, spin-traps and other probes into mitochondria. The moiety itself, while often considered biologically inert, appears to influence mitochondrial metabolism. METHODOLOGY/PRINCIPAL FINDINGS: We used the Seahorse XF flux analyzer to measure the effect of a range of alkylTPP+ on cellular respiration and further analyzed their effect on mitochondrial membrane potential and the activity of respiratory complexes. We found that the ability of alkylTPP+ to inhibit the respiratory chain and decrease the mitochondrial membrane potential increases with the length of the alkyl chain suggesting that hydrophobicity is an important determinant of toxicity. CONCLUSIONS/SIGNIFICANCE: More hydrophobic TPP+ derivatives can be expected to have a negative impact on mitochondrial membrane potential and respiratory chain activity in addition to the effect of the biologically active moiety attached to them. Using shorter linker chains or adding hydrophilic functional groups may provide a means to decrease this negative effect.

• MeSH
• buněčné linie MeSH
• elektronový transportní řetězec metabolismus   MeSH
• heterocyklické sloučeniny farmakologie   MeSH
• krysa rodu rattus MeSH
• membránový potenciál mitochondrií účinky léků   MeSH
• organofosforové sloučeniny farmakologie   MeSH
• potkani Wistar MeSH
• spotřeba kyslíku účinky léků   MeSH
• svalové mitochondrie metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

• Klíčová slova
• metody stanovení množství a ukládání intramyocelulárních lipidů, diabetologický výzkum, perkutánní biopsie kosterního svalu,
• MeSH
• biomedicínský výzkum metody   trendy   MeSH
• diabetes mellitus 2. typu * diagnóza   etiologie   terapie   MeSH
• financování organizované MeSH
• genomika metody   trendy   MeSH
• imunohistochemie metody   trendy   MeSH
• inzulinová rezistence genetika   imunologie   MeSH
• jehlová biopsie * metody   trendy   využití   MeSH
• kosterní svaly * enzymologie   metabolismus   patofyziologie   MeSH
• lidé MeSH
• proteomika metody   trendy   MeSH
• satelitní buňky kosterního svalu cytologie   imunologie   metabolismus   MeSH
• statistika jako téma MeSH
• svalové mitochondrie metabolismus   mikrobiologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• přehledy MeSH