The mitochondrial ATP synthase as an ATP consumer-a surprising therapeutic target.

The mitochondrial F1 Fo -ATP synthase uses a rotary mechanism to synthesise ATP. This mechanism can, however, also operate in reverse, pumping protons at the expense of ATP, with significant potential implications for mitochondrial and age-related diseases. In a recent study, Acin-Perez et al (2023) use an elegant assay to screen compounds for the capacity to selectively inhibit ATP hydrolysis without affecting ATP synthesis. They show that (+)-epicatechin is one such compound and has significant benefits for cell and tissue function in disease models. These findings signpost a novel therapeutic approach for mitochondrial disease.

Rewiring cell signalling pathways in pathogenic mtDNA mutations.

Mitochondria generate the energy to sustain cell viability and serve as a hub for cell signalling. Their own genome (mtDNA) encodes genes critical for oxidative phosphorylation. Mutations of mtDNA cause major disease and disability with a wide range of presentations and severity. We review here an emerging body of data suggesting that changes in cell metabolism and signalling pathways in response to the presence of mtDNA mutations play a key role in shaping disease presentation and progression. Understanding the impact of mtDNA mutations on cellular energy homeostasis and signalling pathways seems fundamental to identify novel therapeutic interventions with the potential to improve the prognosis for patients with primary mitochondrial disease.

Constitutive activation of the PI3K-Akt-mTORC1 pathway sustains the m.3243 A > G mtDNA mutation.

Mutations of the mitochondrial genome (mtDNA) cause a range of profoundly debilitating clinical conditions for which treatment options are very limited. Most mtDNA diseases show heteroplasmy - tissues express both wild-type and mutant mtDNA. While the level of heteroplasmy broadly correlates with disease severity, the relationships between specific mtDNA mutations, heteroplasmy, disease phenotype and severity are poorly understood. We have carried out extensive bioenergetic, metabolomic and RNAseq studies on heteroplasmic patient-derived cells carrying the most prevalent disease related mtDNA mutation, the m.3243 A > G. These studies reveal that the mutation promotes changes in metabolites which are associated with the upregulation of the PI3K-Akt-mTORC1 axis in patient-derived cells and tissues. Remarkably, pharmacological inhibition of PI3K, Akt, or mTORC1 reduced mtDNA mutant load and partially rescued cellular bioenergetic function. The PI3K-Akt-mTORC1 axis thus represents a potential therapeutic target that may benefit people suffering from the consequences of the m.3243 A > G mutation.

Maximal fat oxidation rate in women with sedentary behaviour and at-risk body fat percentage

ABSTRACT The purpose of this study was to examine how the maximal fat oxidation rate is affected in two groups of women with different fat mass percentages. Thirty-four women with sedentary behavior (aged 18-25 years) were divided into 2 groups according to their body fat percentage. (<32% of body fat was considered as a threshold following American College Sport Medicine [ACSM] indications). Body fat percentages were assessed by anthropometry, then subjects performed an adapted graded exercise test on a treadmill to determine maximal oxygen consumption and fat oxidation rates during exercise. There were significant differences (p<0.05) in maximal cardiorespiratory capacity (34.4±4.4 vs 30.4±10.4 mL x kg-1 x min-1) and maximal fat oxidation rates (0.39±0.05 vs 0.31±0.06 g x min-1) between the lower risk group when compared to the higher risk group. There was no correlation between body fat percentage (BF%) and fat oxidation rates in both groups. In conclusion, cardiorespiratory capacity and substrate oxidation are different when two groups of women divided by ACSM recommendations are considered and these results could help clinicians and trainers to prevent weight gain and/or promote body fat and body weight loss.

RESUMEN El propósito de este estudio fue examinar el cambio de la tasa de oxidación de grasas en dos grupos de mujeres con diferentes porcentajes de masa grasa. Metodología: Treinta y cuatro mujeres con comportamiento sedentario (edades de 18 a 25 años) fueron divididas en dos grupos de acuerdo con su porcentaje de masa grasa (<32% fue considerado como umbral siguiendo las indicaciones del American College Sport Medicine [ACSM]). El porcentaje de masa grasa fue medido por antropometría y luego los sujetos realizaron una prueba adaptado en trotadora eléctrica para determinar el consumo máximo de oxígeno y las tasas de oxidación durante el ejercicio. Resultados: Existieron significativas (p<0,05) en la capacidad cardiorrespiratoria (34,4±4,4 vs 30,4±10,4 mL x kg-1 x min-1) y máxima tasa de oxidación de grasas (0,39±0,05 vs 0,31±0,06 g x min-1) entre el grupo de menor riesgo cuando se compara con el de mayor riesgo. No hubo correlación entre el porcentaje de masa grasa (BF%) vs oxidación máxima de grasas. Conclusión: la capacidad cardiorespiratoria y la oxidación de sustratos fue diferente cuando dos grupos de mujeres son divididos por las consideraciones de la ACSM.