From The Structural And (Dys)Function Of ATP Synthase To Deficiency in Age-Related Diseases Pa

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. 

In recent years, more and more studies have shown that there is a close connection between the mitochondrial inner membrane complex and memory. The mitochondrial inner membrane complex is a complex composed of multiple proteins located on the inner mitochondrial membrane. It is mainly responsible for regulating processes such as energy metabolism and cell death in cells. Memory refers to the human brain's ability to learn, remember, and retain external stimuli, experiences, and things. Although the two seem unrelated, recent studies have shown that the mitochondrial inner membrane complex is inextricably linked to memory.

First, the mitochondrial inner membrane complex plays a crucial role in the energy supply of brain cells. When the human body is in a state of high-level thinking, learning, and memory, the brain requires a large amount of energy to maintain normal activity. The mitochondrial inner membrane complex can increase energy levels in cells by regulating glucose metabolism in mitochondria, allowing the brain to operate normally under high-intensity thinking and memory states.

Secondly, the mitochondrial inner membrane complex can also affect memory by regulating ATP synthesis. ATP is an intracellular energy molecule that plays a vital role in the normal functioning of cells. The inner mitochondrial membrane complex regulates the synthesis and level of ATP, so it can affect people's memory by reasonably regulating the level of ATP in the cell. Some related studies have also shown that when the level of ATP in cells is high, people's learning and memory abilities will be significantly improved.

Finally, mitochondrial inner membrane complexes can also influence the death process of brain cells. When brain cells are under greater survival pressure for various reasons, the death process can easily occur. The mitochondrial inner membrane complex can protect the survival of brain cells by regulating mechanisms such as apoptosis and autophagy, thereby maintaining people's memory.

Therefore, the above studies indicate that there is an inextricable connection between mitochondrial inner membrane complexes and memory. By properly regulating the function of the mitochondrial inner membrane complex, people can improve their memory, thereby improving their learning and work efficiency, and leading a better life. It can be seen that we need to improve memory, and Cistanche deserticola can significantly improve memory because Cistanche deserticola is a traditional Chinese medicinal material that has many unique effects, one of which is to improve memory. The efficacy of Cistanche deserticola comes from the multiple active ingredients it contains, including tannic acid, polysaccharides, flavonoid glycosides, etc. These ingredients can promote brain health through a variety of pathways.

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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 such 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 recent cryo-EM studies and by exploring human disease models.

Keywords: mitochondria; ATP synthase; cell death; neurodegenerative diseases.

1. Introduction

Cell survival relies on energy production in the form of ATP (adenosine triphosphate) molecules, the universal energy currency for all living organisms. The mitochondria, known as the cellular powerhouse, are the energy-producing organelles of the cell [1]. 

Unique characteristics are the presence of DNA (mtDNA) exclusively inherited from the mother. The dual control of both nuclear (nDNA) and mtDNA is responsible for encoding around 1500 proteins, playing a role in mitochondrial function and maintenance. 

ATP synthase (EC 3.6.1.34), also known as complex V, is composed of 18 protein subunits, 16 nDNA encoded and two mtDNA encoded. The main function is the conversion of ADP into ATP, thanks to the proton gradient generated by complexes I to IV and activating the rotor mechanism. Being essential in aerobic cells, the basic structure and catalytic mechanisms of ATP synthase are highly conserved across species, from bacteria to eukaryotes [2,3]. 

Moreover, 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 ATP synthase is a key participant in the cell bioenergetic machinery [5] by highlighting the prominent feature of the "enzyme of life". Otherwise, mitochondrial dysfunction may arise from the molecular switch of the ATP synthase function that occurs with the "supernumerary" subunit modification by stimulating different forms of regulated cell death [6]. 

The physio(patho)logical phenomenon might include the Ca2+-dependent permeability transition of the mitochondrial inner membrane to ions and solutes with molecular mass up to about 1.5 KDa [7–9]. Evidence highlights the role of this fascinating enzyme complex as a key molecular and enzymatic switch between cell life and death and increases its attractiveness as a pharmacological target and drug design [10]. 

However, 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]. The increase in the older population in modern society has become a problem in terms of socioeconomic burdens due to higher incidences of age-related neurodegenerative diseases. 

Therefore, the development of new strategies targeting these pathological features is a timely topic. Poor energy homeostasis linked to mitochondrial dysfunction springs from an impaired or defective energy transduction system, which constitutes the main biochemical damage in a variety of genetic and neuropsychiatric diseases [12]. 

In several neurodegenerative diseases, protein aggregation and mitochondrial dysfunction are two pathogenic processes responsible for the onset of age-related diseases. Indeed, mitochondrial structural and functional defects are attributable to mitochondrial dynamics impairment leading to neurodegeneration and aging, Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD). 

The inhibition of excessive fission reduces the cell death pathway triggered by mitochondrial dysfunction [13]. Therefore, the morphology of mitochondria is intimately involved in aging by revealing profound age-dependent changes in membrane architecture. 

The ATP synthase is involved in generating mitochondrial cristae morphology [4]. 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 membrane remodeling triggered by the disassembly of the supramolecular organization of ATP synthase resembles the inner-membrane vesiculation of old mitochondria. In all likelihood, the cristae shorten and collapse with the ATP synthase dimers dissociation that reduces the convex membrane curvature in the inner mitochondrial membrane (IMM). 

Age-related decline in bioenergetics, redox homeostasis, and mitochondrial calcium capacity contribute to accelerating pathogenesis. Indeed, the failure of the organizational power of energy flow in cells is the basis of the biological complexity of diseases in aging [15].

2. The Structure and Function of the ATP Synthase

The ATP synthase is a ubiquitous oligomeric complex placed in the energy-transducing membranes of mitochondria, chloroplasts, and bacteria [16]. The transmembrane protonmotive force (∆p) is employed by ATP synthase as a source of energy. 

The ∆p drives the mechanical rotary mechanism by the membrane-embedded portion of the enzyme (FO) coupled to the chemomechanical synthesis of ATP from ADP and Pi on the hydrophilic F1 portion (Figure 1). Moreover, the ∆p generated by substrate oxidation during the mitochondrial respiration is dissipated by FO with torque generation of the rotor permitting the cooperative ATP binding change mechanism of catalytic sites during ATP production [17]. Conversely, during ATP hydrolysis, the enzyme works in reverse as an H+ pump and re-energizes the IMM. 

This bifunctional energy transmission mechanism of ATP synthase is unique in biological systems [18]. The membrane-bound rotor consists of a c-ring of eight identical helical hairpin structures in close contact with the subunit. 

The c-ring stoichiometry is species-dependent and tightly related to the mitochondrial bioenergetic cost [2,3]. 

Each c subunit has an H+ -binding site defined by a conserved acidic side chain (Glu58 in mammalian) on the C-terminal helix in the middle of IMM that is dicyclohexylcarbodiimide-sensitive and essential in ATP synthesis or hydrolysis. 

The H+ translocation takes place between two aqueous half-channels in a subunit [19], in which asymmetric arrangement dictates the two opposite rotation directions in the ATP synthesis and hydrolysis [20]. The rotation of the c-ring is transmitted directly to the F1 domain by the asymmetrical central stalk (composed of γ, δ, and ε subunit) attached by the "foot" to the c-ring. The γ subunit of the central stalk penetrates along the central axis of the F1 domain that contains three non-catalytic α- and three catalytic β-subunits alternate in a hexameric (αβ)3 structure around the central stalk (Figure 1). 

The catalytic sites are placed on the β subunits at the interface with the α subunits. Each β subunit catalyzes the reaction of synthesis or hydrolysis driven by ∆p or ATP phosphorylation potential, respectively. During the synthesis, the rotation of the rotor view from the matrix side is in anticlockwise mode. Conversely, the clockwise rotation of the rotor supports ATP hydrolysis. 

Each β subunit transforms an ATP molecule in a complete rotation (360◦ ). Therefore, the ATP synthase produces or hydrolyzes three ATP molecules per cycle. This coordinate mechanism is the molecular event of a "Splendid Molecular Machine" supported by a cooperative binding change mechanism of the (αβ)3 structure [21]. Indeed, the catalytic sites can assume three distinct conformations characterized by a different affinity for adenine nucleotide. 

The βTP, βDP, and βE have three nucleotide bound-states: the first has ATP or ATP analogs in the catalytic site, the second has ATP or ADP, and the third has no bound nucleotide. The affinity for adenine nucleotide decreases in the absence of ATP and permits the "closed" conformation with the βTP, βDP states, or "open" state with βE. The enzyme kinetics of the catalytic sites require nucleotide coordination with the essential cofactor Mg2+ [22], which contributes to the catalytic site asymmetry, producing the different affinities for ATP [23]. 

On the contrary, all of the α subunits that are bound to the ATP molecule coordinate with the Mg2+ cofactor and do not undergo chemical transformation. The MgATP bound to the non-catalytic sites has an important role in permitting the detachment of ADP from the β sites. In particular, the ATP hydrolysis forms an βE state loaded with ADP in a "half-closed" conformation that could inhibit the ATP synthase in the absence of MgATP into the non-catalytic sites [24]. Recently, Pinke et al. have revealed a cryo-EM structure of ATP synthase with the natural cofactor Mg2+ substituted in the catalytic sites by the Ca2+ [25]. 

The ATP synthase activated by Ca2+ as a cofactor sustains only the monofunctional activity of ATP hydrolysis, whereas ATP synthesis is not permitted. In inside-out submitochondrial particles, the hydrolysis of ATP in the presence of Ca2+ determines the acridine fluorescence unquenching [26]. Conversely, the ATPase activity is modulated by the ∆p [27]. For these opposite results, the Ca2+-dependent ATP hydrolysis coupled to H+ pumping activity is debated, even if the unidirectional rotational catalysis is retained [28]. 

However, the pathophysiological role of Ca2+-supported ATP hydrolysis should not be investigated in the activity of ATP synthase (un)coupled to H+ translocation, but in the induction of conformational changes that lead to the formation of mPTP [29]. Importantly, a static structure peripheral to the central rotor, which spans the entire ATP synthase length, acts as a stator to prevent the (αβ)3 rotation torque by the central stalk. 

The peripheral stalk (PS) ensures the energy transduction mechanism of the enzyme with the hydrophilic F1 domain enzyme activity coupled to H+ translocation in the hydrophobic FO domain [22,30]. The PS is composed of hydrophilic and hydrophobic subunits. The formers are the oligomycin sensitivity-conferring protein (OSCP), F6, the soluble portion of the b, and d subunit bound to (αβ)3 hexameric structure of the F1 domain, whereas the hydrophobic portion of b and A6L subunits form the embedded portion in the IMM of the PS (Figure 1). 

However, the prevention of idle rotation of the globular catalytic structure of the F1 domain with the rotor is allowed by exploiting the elastic feature of the PS. The interdomain hinge movement of the OSCP can facilitate the flexible coupling of F1 and FO [31].

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