Mitochondrial physiology

As the knowledge base and importance of mitochondrial physiology to evolution, health and disease expands, the necessity for harmonizing the terminology concerning mitochondrial respiratory states and rates has become increasingly apparent. The chemiosmotic theory establishes the mechanism of energy transformation and coupling in oxidative phosphorylation. The unifying concept of the protonmotive force provides the framework for developing a consistent theoretical foundation of mitochondrial physiology and bioenergetics. We follow the latest SI guidelines and those of the International Union of Pure and Applied Chemistry (IUPAC) on terminology in physical chemistry, extended by considerations of open systems and thermodynamics of irreversible processes. The concept-driven constructive terminology incorporates the meaning of each quantity and aligns concepts and symbols with the nomenclature of classical bioenergetics. We endeavour to provide a balanced view of mitochondrial respiratory control and a critical discussion on reporting data of mitochondrial respiration in terms of metabolic flows and fluxes. Uniform standards for evaluation of respiratory states and rates will ultimately contribute to reproducibility between laboratories and thus support the development of data repositories of mitochondrial respiratory function in species, tissues, and cells. Clarity of concept and consistency of nomenclature facilitate effective transdisciplinary communication, education, and ultimately further discovery

Mitochondrial physiology

As the knowledge base and importance of mitochondrial physiology to evolution, health and disease expands, the necessity for harmonizing the terminology concerning mitochondrial respiratory states and rates has become increasingly apparent. The chemiosmotic theory establishes the mechanism of energy transformation and coupling in oxidative phosphorylation. The unifying concept of the protonmotive force provides the framework for developing a consistent theoretical foundation of mitochondrial physiology and bioenergetics. We follow the latest SI guidelines and those of the International Union of Pure and Applied Chemistry (IUPAC) on terminology in physical chemistry, extended by considerations of open systems and thermodynamics of irreversible processes. The concept-driven constructive terminology incorporates the meaning of each quantity and aligns concepts and symbols with the nomenclature of classical bioenergetics. We endeavour to provide a balanced view of mitochondrial respiratory control and a critical discussion on reporting data of mitochondrial respiration in terms of metabolic flows and fluxes. Uniform standards for evaluation of respiratory states and rates will ultimately contribute to reproducibility between laboratories and thus support the development of data repositories of mitochondrial respiratory function in species, tissues, and cells. Clarity of concept and consistency of nomenclature facilitate effective transdisciplinary communication, education, and ultimately further discovery

Modulation of the de novo purine nucleotide pathway as a therapeutic strategy in mitochondrial myopathy

Mitochondrial myopathy (MM) is characterised by muscle weakness, exercise intolerance and various histopathological changes. Recently, a subset of MM has also been associated with aberrant activation of mammalian target of rapamycin complex 1 (mTORC1) in skeletal muscle. This aberrant mTORC1 activation promotes increased de novo nucleotide synthesis, which contributes to abnormal expansion and imbalance of skeletal muscle deoxyribonucleoside triphosphates (dNTP) pools. However, the exact mechanism via which mTORC1-stimulated de novo nucleotide biosynthesis ultimately disturbs muscle dNTP pools remains unclear. In this article, it is proposed that mTORC1-stimulated de novo nucleotide synthesis in skeletal muscle cells with respiratory chain dysfunction promotes an asymmetric increase of purine nucleotides, probably due to NAD+ deficiency. This in turn could disrupt purine nucleotide-dependent allosteric feedback regulatory mechanisms, ultimately leading to dNTP pools aberration. Pharmacological down-modulation of aminoimidazole carboxamide ribonucleotide transformylase/inosine monophosphate cyclohydrolase (ATIC) activity is also proposed as a potential therapeutic strategy in MM exhibiting mTORC1-driven abnormal metabolic reprogramming, including aberrant dNTPs pools

Choice and Sources of Antimalarial Drugs Used for Self-medication in Kisumu, Western Kenya

Background: The choice and sources of antimalarial drugs used for self-medication has important implication to the current malaria treatment policies in Kenya. However, data on the choice of antimalarial drugs used for self-medication and their sources remains scanty. Objectives: The objectives of this study were to determine the prevalence of self-medication, the choice and sources of antimalarial drugs used for malaria self-medication in Kisumu city, Western Kenya. Methodology: This was a cross-sectional community based study, in which semi-structured questionnaires were randomly administered to 338 participants, in five administrative wards of Kisumu city. Results: Overall, 250 (74%) of the participants reported self-medication for perceived malaria illness. Of the 250 participants, 219 (87.6%) had used an antimalarial drug(s), while 31 (12.4%) took other drugs (antipyretics and herbs), which they perceived to have antimalarial effect. Artemisinin-based combination therapies (ACT), was the drug of choice for majority 154 (70.3%) of those who had self-medicated. The other antimalarials used were sulphadoxine/sulphalene-pyrimethamine 25 (11.4%), amodiaquine 11 (5%), chloroquine 5 (2.3%), quinine 2 (0.9%), dihydroartemisinin 1 (0.5%), halofantrene 1 (0.5%) and 20 (9%) of participants had used two different antimalarials. The antimalarial drugs were sourced from private pharmacies/chemists (78.4%), general retail shops (29.2%), left over drugs at home (1.6%), or friends, relatives and neighbors (2.8%). Conclusion: Self-medication for perceived malaria is prevalent in Kisumu city. ACT is the drug of choice for self-medication. However, a substantial proportion of individuals use currently ineffective antimalarials or other drugs, for example antipyretics, with no known antimalarial efficacy. Pharmacies/chemists and general retail shops are the major sources for self-prescribed drugs. Key words: Self-medication, antimalarial drugs, choices, source

Author Response: K320E-Twinkle(skm) Mice Are Genetically Heterogeneous for Secondary mtDNA Deletions Impairing Comparison With Controls

International audienc

Lumefantrine-resistant and Piperaquine-resistant Plasmodium berghei show cross-resistance to Primaquine but not to Atovaquone

Background: Malaria affects 300-500 million people annually and kills more than 1 million, with majority of the clinical cases and deaths occurring in Sub-Saharan Africa. Rapid development of drug resistance remains a major challenge in malaria control and has lead to use of combined antimalarial therapies. Resistance to an antimalarial drug may however, be selected for by another drug in which the mechanism of resistance is similar. Objective: This study sought to establish cross-resistance patterns between four antimalarials namely atovaquone (ATQ), primaquine (PMQ), lumefantrine (LM) and piperaquine (PQ) using murine malaria models. Method: The activities of ATQ and PMQ against drug sensitive, PQ and LM-resistant Plasmodium berghei lines was assessed using the 4-day test and 90% index of resistance (I90) determined. Results: Analysis of cross-resistance patterns showed a significant decrease in PMQ sensitivity (I90 of 6.39), and a slight but not significant decrease in ATQ (I90 of 1.19) activity towards the LM-resistant P.berghei ANKA. Conclusion: PQ-resistance in P. berghei is associated with a significant resistance of PMQ (I90 of 12.22) and a slight, though not significant reduction in ATQ (I90 of 1.27) efficacy. Key words: Plasmodium berghei, resistance, piperaquine, lumefantrine, primaquine, atovaquon

Combined fibre atrophy and decreased muscle regeneration capacity driven by mitochondrial DNA alterations underlie the development of sarcopenia

International audienc

Epithelial loss of mitochondrial oxidative phosphorylation leads to disturbed enamel and impaired dentin matrix formation in postnatal developed mouse incisor

The formation of dentin and enamel matrix depends on reciprocal interactions between epithelial-mesenchymal cells. To assess the role of mitochondrial function in amelogenesis and dentinogenesis, we studied postnatal incisor development in K320E-Twinkle(Epi) mice. In these mice, a loss of mitochondrial DNA (mtDNA), followed by a severe defect in the oxidative phosphorylation system is induced specifically in Keratin 14 (K14+) expressing epithelial cells. Histochemical staining showed severe reduction of cytochrome c oxidase activity only in K14+epithelial cells. In mutant incisors, H&E staining showed severe defects in the ameloblasts, in the epithelial cells of the stratum intermedium and the papillary cell layer, but also a disturbed odontoblast layer. The lack of amelogenin in the enamel matrix of K320E-Twinkle(Epi) mice indicated that defective ameloblasts are not able to form extracellular enamel matrix proteins. In comparison to control incisors, von Kossa staining showed enamel biomineralization defects and dentin matrix impairment. In mutant incisor, TUNEL staining and ultrastructural analyses revealed differentiation defects, while in hair follicle cells apoptosis is prevalent. We concluded that mitochondrial oxidative phosphorylation in epithelial cells of the developed incisor is required for Ca2+homeostasis to regulate the formation of enamel matrix and induce the differentiation of ectomesenchymal cells into odontoblasts