From the Structural and (Dys)Function of ATP Synthase to Deficiency in Age-Related Diseases.

Caterina Garone,Salvatore Nesci,Andrea Pietra

doi:10.3390/life12030401

Abstract

The ATP synthase is a mitochondrial inner membrane complex whose function is essential for cell bioenergy, being responsible for the conversion of ADP into ATP and playing a role in mitochondrial cristae morphology organization. The enzyme is composed of 18 protein subunits, 16 nuclear DNA (nDNA) encoded and two mitochondrial DNA (mtDNA) encoded, organized in two domains, FO and F1. Pathogenetic variants in genes encoding structural subunits or assembly factors are responsible for fatal human diseases. Emerging evidence also underlines the role of ATP-synthase in neurodegenerative diseases as Parkinson’s, Alzheimer’s, and motor neuron diseases such as Amyotrophic Lateral Sclerosis. Post-translational modification, epigenetic modulation of ATP gene expression and protein level, and the mechanism of mitochondrial transition pore have been deemed responsible for neuronal cell death in vivo and in vitro models for neurodegenerative diseases. In this review, we will explore ATP synthase assembly and function in physiological and pathological conditions by referring to the recent cryo-EM studies and by exploring human disease models.

Highlights

Received: 15 February 2022Cell survival relies on energy production in the form of ATP molecules, the universal energy currency for all living organisms
Cerevisiae have demonstrated that mitochondrial DNA (mtDNA) segregation requires a continuous mitochondrial network and ATP synthase dimers stand in close proximity of mtDNA creating a compartment where different mtDNA molecules are not mixed. This “compartmentalization” is responsible for the negative selection of mutant mtDNA molecules that cannot be complemented by wild-type mtDNA molecules and create a dysfunctional bioenergetic environment that leads to mtDNA purging [39]
Mitochondrial integrity and function are crucial for the proliferation, differentiation, Mitochondrial integrity and (NSCs) function are crucial for theDuring proliferation, differentiation, and maintenance of neural stem cells in health and disease

Summary

Introduction

Cell survival relies on energy production in the form of ATP (adenosine tri-phosphate) molecules, the universal energy currency for all living organisms. ATP synthase (EC 3.6.1.34), known as complex V, is composed of 18 protein subunits, 16 nDNA encoded and two mtDNA encoded. The enzyme is involved in the morphology of mitochondria by contributing to the generation of inner membrane cristae, an event that evolves to include membrane “supernumerary” subunits [4]. The mitochondrial dysfunction may arise from the molecular switch of the ATP synthase function that occurs with the “supernumerary” subunits modification by stimulating. Mitochondria can take part in both the development and cell death process, in which features are dependent on the phenomenon that forms a high-conductance channel known as mitochondrial permeability transition pore (mPTP) [11]. ATP synthase dimers are arranged in long rows on the tip of cristae together with the MICOS (mitochondrial contact site and cristae organizing system) complex at cristae junctions and cooperate by opposing effects on membrane curvature to the cristae morphology [14]. The failure of the organisational power of energy flow in cells is the basis of the biological complexity of diseases in ageing [15]

The Structure and Function of the ATP Synthase

The Hidden Face of the ATP Synthase

The ATP Synthase Deficiency

Neurodegeneration

Conclusions