Targeting The Mitochondrial Permeability Transition Pore To Prevent Age-Associated Cell Damage And Neurodegeneration Part 1

The aging process is associated with significant alterations in mitochondrial function. These changes in mitochondrial function are thought to involve increased production of reactive oxygen species (ROS), which over time contribute to cell death, senescence, tissue degeneration, and impaired tissue repair.

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 The mitochondrial permeability transition pore (mPTP) is likely to play a critical role in these processes, as increased ROS activates mPTP opening, which further increases ROS production. 

Injury and inflammation are also thought to increase mPTP opening, and chronic, low-grade inflammation is a hallmark of aging. Nicotinamide adenine dinucleotide (NAD+) can suppress the frequency and duration of mPTP opening; however, NAD+ levels are known to decline with age, further stimulating mPTP opening and increasing ROS release. 

Research on neurodegenerative diseases, particularly Parkinson's disease (PD) and Alzheimer's disease (AD), has uncovered significant findings regarding mPTP openings and aging. Parkinson's disease is associated with a reduction in mitochondrial complex I activity and increased oxidative damage of DNA, both of which are linked to mPTP opening and subsequent ROS release. 

Similarly, AD is associated with increased mPTP openings, as evidenced by amyloid-beta (Aβ) interaction with the pore regulator cyclophilin D (CypD). 

Targeted therapies that can reduce the frequency and duration of mPTP opening may therefore have the potential to prevent age-related declines in cell and tissue function in various systems including the central nervous system.

1. Introduction

The number of older adults is growing worldwide. As a result, the incidence of age-associated diseases including AD, osteoporosis, sarcopenia, and osteoarthritis is also increasing. 

This increase in age-related disorders has a significant, negative impact on the quality of life for patients and their families and also places a substantial burden on healthcare systems. 

A better understanding of the cellular and molecular mechanisms underlying aging is central to the successful development and clinical translation of novel therapies and prevention strategies. 

Recent work has demonstrated that changes in mPTP function may contribute directly to cellular dysfunction with aging [1–3]. These changes include increases in ROS production, induction of cellular senescence (particularly in aging stem cells), and activation of the inflammasome, the latter contributing directly to the chronic state of inflammation often referred to as "inflammaging" [1–3]. 

mPTP dysfunction has been cited as a key factor in neurodegenerative pathologies through its role in collapsing mitochondrial membrane potential, repressing mitochondrial respiratory function, releasing mitochondrial Ca2+ and cytochrome c, and enhancing ROS generation [4– 7]. Thus, the mPTP has received increased attention as a potential therapeutic target. 

The relationship between the mPTP and the generation of mitochondrial reactive oxygen species (mROS) has attracted significant interest within the context of aging and age-related tissue degeneration [8]. 

Recently, it was found that mROS can stimulate the opening of the mPTP, which can lead to further mROS production and release [9]. This positive feedback mechanism ultimately leads to an excessive amount of ROS accumulation. ROS accumulation in turn damages nuclear DNA, activates proapoptotic signaling pathways, and drives cellular aging [10–12]. 

On the other hand, ROS can in some cases activate protective pathways, decrease stress on the mitochondria, and increase lifespan [1, 11]. It is currently thought that the mPTP plays an important role in integrating the effects of mROS and hence may play a vital role in the aging process [8]. 

In this review, we discuss the various mechanisms inducing activation of the mPTP and the age-associated cell damage seen as a byproduct of mPTP activation. Furthermore, we discuss potential therapies that target the mPTP and may therefore inhibit the effects of aging and injury.

1.1. Structure and Formation of the mPTP.

Various structural components of the mPTP are implicated in permeability transition (PT); however, the overall structure of the mPTP is still not completely understood. 

It was previously thought that the pore consisted of several components including a voltage-dependent ion channel (VDAC), an adenine nucleotide transporter (ANT), and a peripheral benzodiazepine receptor [13, 14]. 

These elements are described to perform specific roles: VDAC is associated with the benzodiazepine receptor and regulates the extramitochondrial transfer of cholesterol to the intermembrane space whereas ANT permits the inflow of phosphorylated and nonphosphorylated derivatives of adenine nucleotides [15]. 

Except for ANT, which is thought to act as a potential regulatory molecule, recent genetic experiments have ruled out the aforementioned elements as components of the mPTP [16]. 

Thus, we present here the most recent models regarding mPTP composition with the understanding that these may be revised shortly. Recent models of pore composition posit that the F1F0 (F)-ATP synthase is the main component of the pore and that the regulatory molecule CypD is a protein modulator of the mPTP [17]. 

In this model, the mPTP originates from a conformational change occurring on the F1F0 (F)-ATP synthase after Ca2+ binding, possibly by replacing Mg2+ at the catalytic site [18]. 

Whether the dimeric form or the monomeric form of F1F0 (F)-ATP synthase is necessary to increase PT is still of great debate [19, 20]. Nevertheless, F1F0 (F)-ATP synthase's status as a pore component is supported by genetic manipulation of F1F0 (F)-ATP synthase [20, 21], by electrophysiological measurements [20, 22–24], and by mutagenesis of specific residues of F1F0 (F)-ATP synthase [18, 25–27]. 

On the other hand, Walker and colleagues have proposed that the F1F0 (F)-ATP synthase is not an essential component of the pore [28, 29]. Their hypothesis is based on the observation that even after ablating subunits b and OSCP of F1F0 (F)-ATP synthase, mitochondrial PT still occurred [29]. 

Matrix swelling was used to determine PT because long-lasting mPTP opening in vitro is followed by solute diffusion with matrix swelling [30]. Questions have, however, been raised regarding these findings. Bernardi [17] in particular noted the absence of replicates and calibration with pore-forming agents like alamethicin may complicate interpretation of the data. 

The effects on respiration following F1F0 (F)-ATP synthase knockout raise additional questions. Respiratory activity was dramatically decreased to between 10 and 20% of the rate observed in wild-type cells after F1F0 (F)-ATP synthase knockout [29]. The driving force in respiring mitochondria for Ca2+ accumulation is the inside-negative membrane potential generated by respiration [31, 32]. 

Furthermore, Ca2+ uptake is charge-compensated by increased H+ pumping by the respiratory chain [17]. Thus, it is important to note that the maximal rate of Ca2+ uptake is limited by the maximal rate of H+ pumping by the respiratory chain [33]. 

When extramitochondrial Ca2+ levels exceed 2 μM, the latter becomes rate-limiting [34]. He et al. [28] used 10 μM pulses of Ca2+ to induce PT; therefore, Ca2+ uptake by mitochondria lacking subunits c, b, and OSCP should have been significantly lower and not identical to wild-type mitochondria [17]. This raises questions about the Ca2+ retention capacity, a measurement used by He et al. [28] to determine mPTP opening. 

It is possible that respiratory inhibition due to the absence of certain subunits may not be constant over time. 

Potential mechanisms may exist that restore the expression of F1F0 (F)-ATP synthase and as a consequence the respiratory chain. When considering the above findings, F1F0 (F)-ATP synthase cannot necessarily be ruled out as a pore component.

The most compelling experiments supporting F1F0 (F)- ATP synthase as a pore component focus on the mutagenesis of specific residues of F-ATP synthase. Specifically, it was found that matrix H+ leads to inhibition of mPTP and complete channel block at pH 6.5 [25, 35]. 

It was found that the mPTP block is mediated by reversible protonation of matrix-accessible His residues [35]. Recently, H112 of the OSCP subunit has been implicated as the unique His responsible for the PTP block by H+ [25]. 

Although these findings are intriguing concerning mPTP activity, they serve a dual purpose in also supporting OSCP and as a consequence F1F0 (F)-ATP synthase as potential components of the mPTP. Further controversial components include ANT, which may serve a regulatory role by binding CypD and reconstituting into proteoliposomes, producing Ca2+-activated pores similar to the mPTP [36, 37] and the mitochondrial phosphate carrier PiC [38, 39]. Thus, potential constituents of the mPTP include ANT, PiC, and F1F0 (F)-ATP synthase (Figure 1). 

Although its role is controversial, we emphasize the potential role of F1F0 (F)-ATP synthase in mitochondrial permeability. F1F0 (F)-ATP synthase's various interactions with molecules such as CypD result in increased mitochondrial permeability. 

The specific subunits of F1F0 (F)-ATP synthase have been studied for their interaction with regulatory molecules such as CypD. It is thought that mammalian F1F0 (F)-ATP synthase is a protein complex composed of the following: an F1 region composed of (αβ)3, γ, δ, and ε subunits, which protrudes in the matrix and synthesizes/hydrolyzes ATP; an F0 sector, formed from a subunit, the c8- ring, two membrane-inserted α-helices of b subunit, and supernumeraries subunits e, f, g, k, A6L, diabetes-associated protein in insulin-sensitive tissue (DAPIT) and 6.8 kDa proteolipid, which allows H+ flow across the IMM; the central stalk complex; and the peripheral stalk subcomplex composed of the following: oligomycin sensitivity conferral protein (OSCP), d, F6, and the extrinsic α-helices of A6L and b subunits (Figure 1) [40].

Figure 1: Prevailing model concerning the makeup of the mPTP as formed by the following potential components: mammalian F1F0 (F)-ATP synthase, Adenine nucleotide translocator (ANT), and mitochondrial phosphate carrier (PiC). 

The figure is redrawn and adapted based on reference [138]. Although ANT and PiC remain controversial potential components of the mPTP, they are shown as both red and green components overlaying the inner mitochondrial membrane (IMM). 

Similarly, although F1F0 (F)- ATP synthase is a controversial component, it is labeled as follows. Subunits of the F0 component labeled in purple include a, e, f, g, and A6L. F1 components include α and β subunits labeled in yellow and red, respectively. 

The C ring subunit is labeled in blue represented by a cylinder. The F1 peripheral stalk is composed of the subunits b, d, F6, and oligomycin sensitivity conferring protein (OSCP) labeled represented by a peach rectangle, a blue rectangle, and a blue circle, respectively. 

The mPTP is the point at which ROS, Ca2+, and other molecules can escape from the matrix of the mitochondria.

OSCP and CypD interact to promote the opening of the mPTP, and further, mPTP opening is increased with aging and oxidative stress [41–43]. Oxidative stress induces the translocation of the tumor suppressor p53 to the mitochondrial matrix where it interacts with CypD to aid in the formation of the mPTP [44]. 

Like the oxidative stress-induced formation of the mPTP, Ca2+ can also induce the formation of the mPTP. It has been found that soluble matrix peptidylprolyl isomerase F cyclophilin D (PPIF) is involved in the Ca2+-induced opening of the mPTP [15]. 

The interaction between the aforementioned molecules, oxidative stress, and Ca2+ overloading can change significantly across the lifespan.

1.2. Role of the mPTP in Cellular Aging.

A range of studies indicates that mPTP activation is altered with age in a variety of cell and tissue types. These include permeabilized myofibrils in humans [45], myocytes in rats [46], and osteocytes in mice [47]. 

It should be noted, before discussing the various effects of aging on mPTP activation, that Ca2+ is a well-established activator of the mPTP [48]. Specifically, concerning the permeabilized myofibrils in humans, Gouspillou et al. [28] found that Ca2+ retention and time to mPTP opening were significantly decreased in skeletal muscle of older active men [45]. 

Decreased Ca2+ retention is indicative of mPTP openings [45]. It was also found that the mPTP of older, active men maintains an increased sensitivity to Ca2+, further supporting the idea that increased mPTP activation is a byproduct of aging. 

These results are further reinforced by work showing that oxidative damage to Ca2+ transporters leads to Ca2+ leakage into the cytosol and subsequent mitochondrial matrix Ca2+ overloading, which then leads to activation of the mPTP [49, 50]. 

Activation of the mPTP can also be seen as a product of increased ROS production. Notably, ROS production increases with age [51], and it is thought that ROS production is increased in complexes I and III with the inhibition of electron transport [52]. Oxidative damage to mtDNA and/or electron transport complexes is suggested to result in defective ROS-producing complexes. 

A cycle is established in which ROS produced by damaged mtDNA and/or electron transport complexes further damages electron transport complexes with age [51] (Figure 2). 

The increase in ROS production with age is noteworthy because increased mPTP activation is associated with elevated levels of ROS. This is based on the study conducted by Zorov and colleagues, who found that ROS accumulation within the mitochondria of cardiac myocytes leads to increased mitochondrial permeability transition and release of ROS from the mitochondria (ROS-induced ROS release) [53]. 

Thus, a clear relationship between age, elevated ROS levels, and increased mPTP openings is established. 

As will be discussed later, ROS released from the mitochondria can damage nuclear DNA and lead to proapoptotic signals which increase mPTP openings [54– 56]. Due to the scope of this article, changes in the respiratory chain with aging will not be discussed further.

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