Mitochondrial ATP synthase: architecture, function and pathology

Human mitochondrial (mt) ATP synthase, or complex V consists of two functional domains: F1, situated in the mitochondrial matrix, and Fo, located in the inner mitochondrial membrane. Complex V uses the energy created by the proton electrochemical gradient to phosphorylate ADP to ATP. This review covers the architecture, function and assembly of complex V. The role of complex V di-and oligomerization and its relation with mitochondrial morphology is discussed. Finally, pathology related to complex V deficiency and current therapeutic strategies are highlighted. Despite the huge progress in this research field over the past decades, questions remain to be answered regarding the structure of subunits, the function of the rotary nanomotor at a molecular level, and the human complex V assembly process. The elucidation of more nuclear genetic defects will guide physio(patho)logical studies, paving the way for future therapeutic interventions

The potential role of mitochondrial ATP synthase inhibitory factor 1 (IF1) in coronary heart disease: a literature review

Cardiovascular disease (CVD) is the leading cause of death worldwide, and so the search for innovative and accurate biomarkers for guiding prevention, diagnosis, and treatment is a valuable clinical and economic endeavor. Due to a recent findings that the serum concentration of mitochondrial ATP synthase inhibitory factor 1 (IF1) is an independent prognostic factor in patients with coronary heart disease (CHD), we reviewed the role of this protein in myocardial ischemic preconditioning, its correlation to plasma high density lipoprotein (HDL), the predictive potential in patients with CHD, and its interplay with angiogenesis. IF1 has been positively correlated with plasma HDL-cholesterol, and is independently negatively associated with all-cause and CV mortality in patients with CHD. However, this conclusion is prevalently based on limited data, and more research is needed to draw definitive conclusions. IF1 seems to play an additional role in increasing cell vulnerability in oncologic diseases but may also function as modest inhibitor of angiogenesis in physiological conditions. It has been also explored that IF1 may rather act as a modulator of other molecules more significantly involved in angiogenesis, especially apolipoprotein A1 on which the largest effect could be observed. In conclusion, more research is needed to characterize the role of IF1 in patients with CHD

Cost-effectiveness analysis of second-line pharmacological treatment of acromegaly in Spain

Objective: To estimate the cost-effectiveness of second-line pharmacological treatments in patients with acromegaly resistant to first-generation somatostatin analogues (FG SSA) from the Spanish National Health System (NHS) perspective.Methods: A Markov model was developed to analyze the cost-effectiveness of pegvisomant and pasireotide in FG SSA-resistant acromegaly, simulating a cohort of patients from the treatment beginning to death. Treatment with pegvisomant or pasireotide was compared to FG SSA retreatment. Efficacy data were obtained from clinical trials and utilities from the literature. Direct health costs were obtained from Spanish sources (euro2018).Results: The Incremental Cost Effectiveness Ratio (ICER) of pegvisomant vs. FG SSA was euro85,869/Quality-adjusted life years (QALY). The ICER of pasireotide vs. FG SSA was euro551,405/QALY. The ICER was mainly driven by the incremental efficacy (4.41 QALY for pegvisomant vs. FG SSA and 0.71 QALY for pasireotide vs. FG SSA), with a slightly lower increase in costs with pegvisomant (euro378,597 vs. FG SSA) than with pasireotide (euro393,151 vs. FG SSA).Conclusion: The ICER of pasireotide compared to FG SSA was six times higher than the ICER of pegvisomant vs. FG SSA. Pegvisomant is a more cost-effective alternative for the treatment of acromegaly in FG SSA-resistant patients in the Spanish NHS