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The ATP Synthase Deficiency in Human Diseases

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The ATP Synthase Deficiency in Human Diseases life Review The ATP Synthase Deficiency in Human Diseases Chiara Galber 1,2, Stefania Carissimi 1, Alessandra Baracca 2 and Valentina Giorgio 1,2,* 1 Consiglio Nazionale delle Ricerche, Institute of Neuroscience, I-35121 Padova, Italy; [email protected] (C.G.); [email protected] (S.C.) 2 Department of Biomedical and Neuromotor Sciences, University of Bologna, I-40126 Bologna, Italy; [email protected] * Correspondence: [email protected] Abstract: Human diseases range from gene-associated to gene-non-associated disorders, including age-related diseases, neurodegenerative, neuromuscular, cardiovascular, diabetic diseases, neurocog- nitive disorders and cancer. Mitochondria participate to the cascades of pathogenic events leading to the onset and progression of these diseases independently of their association to mutations of genes encoding mitochondrial protein. Under physiological conditions, the mitochondrial ATP synthase provides the most energy of the cell via the oxidative phosphorylation. Alterations of oxidative phosphorylation mainly affect the tissues characterized by a high-energy metabolism, such as nervous, cardiac and skeletal muscle tissues. In this review, we focus on human diseases caused by altered expressions of ATP synthase genes of both mitochondrial and nuclear origin. Moreover, we describe the contribution of ATP synthase to the pathophysiological mechanisms of other human diseases such as cardiovascular, neurodegenerative diseases or neurocognitive disorders. Keywords: ATP synthase; human disease; mitochondria Citation: Galber, C.; Carissimi, S.; Baracca, A.; Giorgio, V. The ATP Synthase Deficiency in Human 1. Introduction Diseases. Life 2021, 11, 325. Mitochondria support aerobic respiration and produce the majority of cellular ATP https://doi.org/10.3390/ by oxidative phosphorylation (OXPHOS) [1]. Electrons derived from the oxidation of life11040325 fatty acids, carbohydrates and amino acids are shuttled to oxygen along the respiratory chain complexes (I–IV) embedded in the inner mitochondrial membrane (IMM), producing Academic Editor: Gopal J. Babu; water and releasing the energy necessary to pump protons from the mitochondrial ma- Giorgio Lenaz and Salvatore Nesci trix to the intermembrane space (IMS). This results in the formation of a transmembrane electrochemical gradient across the IMM, which enables the ATP synthase to produce Received: 8 March 2021 ATP from ADP and inorganic phosphate [2]. A reverse catalytic process can occur under Accepted: 3 April 2021 Published: 8 April 2021 anoxia, a condition in which ATP synthase couples ATP hydrolysis to the generation of a transmembrane potential [3,4]. The mitochondrial OXPHOS is the only metabolic Publisher’s Note: MDPI stays neutral pathway that is under dual genetic control. It is therefore possible to distinguish genetic ∼ with regard to jurisdictional claims in defects caused by (i) alterations in mitochondrial DNA (mtDNA), 15%, e.g., Neuropathy, published maps and institutional affil- Ataxia, Retinitis Pigmentosa (NARP), Maternally Inherited Leigh’s Syndrome (MILS) and iations. Leber’s Hereditary Optic Neuropathy (LHON) [5] and (ii) nuclear DNA (nDNA) mutations, which are inherited as Mendelian disorders. A recent review provided an update on the contribution of nuclear genes that impair mitochondrial respiration in patients and have been characterized in yeast [6]. More than 150 distinct genetic mitochondrial dysfunction syndromes characterized by a diminished OXPHOS capacity have been described [5,7–11]. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. Typical clinical traits include visual/hearing defects, encephalopathies, cardiomyopathies, This article is an open access article myopathies, diabetes, liver and renal dysfunctions [12–14]. In other cases, mitochondria distributed under the terms and participate to the cascades of pathogenic events leading to the onset of several diseases, conditions of the Creative Commons but they are not linked to their genetic origins. Mitochondria are damaged during the Attribution (CC BY) license (https:// reperfusion of ischemic heart, age-related diseases and all the major neurodegenerative creativecommons.org/licenses/by/ diseases—-Parkinson’s (PD), Alzheimer’s (AD) and motor neuron diseases such as Amy- 4.0/). otrophic Lateral Sclerosis (ALS). Life 2021, 11, 325. https://doi.org/10.3390/life11040325 https://www.mdpi.com/journal/life Life 2021, 11, x FOR PEER REVIEW 2 of 20 Life 2021, 11, 325 diseases––Parkinson’s (PD), Alzheimer’s (AD) and motor neuron diseases such as Amy-2 of 19 otrophic Lateral Sclerosis (ALS). In this scenario, ATP synthase has been shown to participate to the pathogenesis of different human diseases. The mitochondrial enzyme occupies the IMM of the organelle In this scenario, ATP synthase has been shown to participate to the pathogenesis of and forms dimers. Each monomeric unit (Figure 1), as shown in the latest dimeric mam- different human diseases. The mitochondrial enzyme occupies the IMM of the organelle malian enzyme by electron cryo-microscopy [15], is an assembly of 28 polypeptide chains and forms dimers. Each monomeric unit (Figure1), as shown in the latest dimeric mam- of 17 different subunits organized into a catalytic globular domain, which is attached to malian enzyme by electron cryo-microscopy [15], is an assembly of 28 polypeptide chains an intrinsic membrane domain by a central stalk and a peripheral stalk [16]. This mem- of 17 different subunits organized into a catalytic globular domain, which is attached to an brane-bound enzyme is a rotary machine. The membrane-bound rotor consists of eight intrinsic membrane domain by a central stalk and a peripheral stalk [16]. This membrane- identical c subunits (c- ring) in close association with a single a (or ATP6) subunit and is bound enzyme is a rotary machine. The membrane-bound rotor consists of eight identical attached to the asymmetrical central stalk (subunits γ, δ and e) [17,18], which extends from c subunits (c- ring) in close association with a single a (or ATP6) subunit and is attached theto membrane the asymmetrical domain centraland penetrates stalk (subunits into the γextrinsic, δ and e)globular [17,18], catalytic which extends domain from along the its membranecentral axis domain. As the andcentral penetrates stalk rotates, intothe it causes extrinsic structural globular changes catalytic in domainthe three along cata- its lyticcentral sites, axis.found As mainly the central in each stalk of the rotates, three it β causes subunits, structural which changesalternate in with the three three α catalytic sub- unitssites, in foundthe spherical mainly inextrinsic each of domain the three [16,19β subunits,]. These which structural alternate changes with lead three toα thesubunits en- zyme’sin the catalytic spherical activity. extrinsic The domain peripheral [16,19 stalk,]. These composed structural of the changes subunits lead oligomycin to the enzyme’s sen- sitivitycatalytic conferral activity. protein The peripheral(OSCP), b, stalk,d, F6 composedand the membrane of the subunits extrinsic oligomycin region of sensitivityA6L (or ATP8),conferral links proteinthe external (OSCP), surface b, d, of F6 the and catalytic the membrane domain (F extrinsic1) to the regiona subunit ofA6L in the (or mem- ATP8), brane domain (Fo) [20,21]. The subunits e, f, g, A6L and 6.8 proteolipid also contribute to links the external surface of the catalytic domain (F1) to the a subunit in the membrane thedomain membrane (Fo)[ domain20,21]. of The the subunits peripheral e, f, stalk g, A6L [22– and24], 6.8 and proteolipid in the dimeric also complex contribute, some to the of membranethem are involved domain in of forming the peripheral the interface stalk [between22–24], and monomers in the dimeric [24]. Another complex, subunit, some of previouslythem are kno involvedwn as diabetes in forming-associated the interface protein between in insulin monomers sensitive- [tissues24]. Another (DAPIT) subunit, [23], maypreviously be involved known in the as formation diabetes-associated of links between protein dimer in insulin units sensitive-tissues in the rows of dimers (DAPIT) [25] [23. ], In maythis review, be involved we mainly in the formationfocus on mutations of links between in mitochondrial dimer units and in nuclear the rows genes of dimers encod- [25]. ingIn ATP this synthase review, we subunits mainly and focus factors on mutations important in for mitochondrial their associat andion to nuclear human genes diseases. encod- Moreover,ing ATP we synthase describe subunits the contribution and factors of important this enzyme for theirto the association pathogenic to mechanisms human diseases. of cardiovascular,Moreover, we neurodegenerative describe the contribution diseases of and this neurodevelopmental enzyme to the pathogenic disorders. mechanisms Due to of spacecardiovascular, constraints, neurodegenerativethe modulation and diseases regulation and of neurodevelopmental the ATP synthase in disorders.cancer has Due not to beenspace addressed constraints, in this the review modulation; however and, for regulation details, see of the[26,27 ATP]. synthase in cancer has not been addressed in this review; however, for details, see [26,27]. Figure 1. Subunit composition of the bovine ATP synthase monomer is mapped according to [15], (Protein Data Bank (PDB): 6ZQM). In the upper part, the subunits α(3) and β(3) of the catalytic domain are red and yellow, respectively; the three
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