Reappraisal Of Metabolic Dysfunction in Neurodegeneration: Focus On Mitochondrial Function And Calcium Signaling Part 2

control, protein aggregation, progressive cellular dysfunction, and neurodegeneration. Several of the mitochondrial dehydrogenases mentioned above (PDH, α-KGDH, and ICDH) are known to be regulated by the Ca2+ concentration within the mitochondrial matrix [63–65]. 

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The reactions catalyzed by the Ca2+-regulated mitochondrial dehydrogenases are rate-limiting steps in the TCA cycle, and therefore free-Ca2+ content in the mitochondrial matrix is a major regulator of metabolic output. 

PDH activity increases upon dephosphorylation of its E1α subunit, which is mediated by the Ca2+-sensitive phosphatase (PDP1) [64]. In neurons, Ca2+ influx through voltage-dependent Ca2+ channels is required for the fusion of synaptic vesicles with the plasma membrane and the release of neurotransmitters at the synaptic cleft [66, 67]. 

Neuronal communication through synaptic transmission is an energy-demanding process, and mitochondria have a critical role in this process by providing ATP (via OxPhos) and by buffering synaptic Ca2+/i Ca2+ to modulate neurotransmitter release [68]. 

The efficient regulation and buffering of I Ca2+ is critical to prevent neuronal excitotoxicity. Mitochondria and the endoplasmic reticulum (ER) both are significant modulators of I Ca2+ signaling and the role of ER in neuronal I Ca2+ buffering is well known [69, 70]. 

However, our understanding of mCa2+ buffering in neurons is limited and evolving. Ca2+ enters the mitochondrial matrix through the mitochondrial calcium uniporter channel (mtCU) [71, 72] and is extruded via the mitochondrial Na+/Ca2+  exchanger (NCLX) [73, 74]. 

Any dysfunction in mCa2+ exchange or matrix bufering capacity can lead to impairments in mitochondrial Ca2+ homeostasis resulting in mCa2+ overload, oxidative stress, metabolic dysfunction, and cell death that can cause or precede AD pathology [75–78]. 

We and others have reported that mitochondrial and metabolic dysfunction is a primary contributor to AD pathogenesis, with dysfunction observable before the appearance of Aβ aggregates and NFTs [18, 77, 79, 80]. 

We found alterations in the expression of mCa2+ handling genes in samples isolated from the brains of SAD patients post-mortem and in the triple transgenic mouse model of AD (3xTg-AD) before observable AD pathology [77]. 

Our observations suggest that mCa2+ overload caused by an age-dependent remodeling of mCa2+ exchange machinery contributes to the progression of AD by promoting metabolic and mitochondrial dysfunction. 

We also found a decrease in OxPhos capacity in APPswe cell lines (K670N, M671L Swedish mutation), providing further evidence of impaired mitochondrial metabolism in AD [77]. 

Importantly, the genetic rescue of neuronal mCa2+ efflux capacity by expression of NCLX in 3xTg-AD mice was sufficient to block age-dependent AD-like pathology [77]. 

Employing quantitative comparative proteomics strategies in AD mice, other groups have reported significant alterations in the mitochondrial proteome, including the citric acid cycle, OxPhos, pyruvate metabolism, glycolysis, oxidative stress, ion transport, apoptosis, and mitochondrial protein synthesis well before the onset of the AD phenotype [79–81]. 

Further evidence of mCa2+ dysregulation is from metabolomics in an Aβ-transgenic C. elegans model (GRU102), wherein the authors showed a reduction in TCA cycle flux before the appearance of significant Aβ deposition, with the greatest reduction observed in α-KGDH activity. 

Knockdown of α-KGDH in control worms elicited reductions in both basal and maximal respiration like that observed in the AD worm model [18]. 

These observations suggest that reduced α-KGDH activity alone is sufficient to recapitulate the metabolic deficits observed in AD and is in line with a study by Yao et al. [46] wherein 3-month-old 3xTg-AD mice were found to have reduced mitochondrial respiration and PDH activity, coupled with increased ROS generation [46]. Altogether, these data indicate that mCa2+ dysregulation is likely an early event in AD. 

Mitochondria are highly dynamic, and exhibit cell type-specific metabolism in the brain [37, 82]. Axonal mitochondria appear small and sparse whereas dendritic mitochondria are elongated and more densely packed [82]. 

To ensure an appropriate energy supply, especially in distal regions of the axons, mitochondria must be properly positioned. Indeed, mitochondria undergo bi-directional axonal transport including anterograde transport  (from cell body to axon) and retrograde transport  (from axon to cell body) [83, 84]. 

Axonal transport is mediated by ATP‐hydrolyzing motor proteins (kinesin‐I for anterograde and dynein for retrograde) to move cargo along microtubule tracks [85] and defects in transport seem to present before evident AD hallmarks [86, 87]. 

Defects in anterograde transport result in an insufficient supply of ATP at the synapse, resulting in synaptic starvation and dysfunction, an early pathological feature of AD [36]. 

Similarly, defective retrograde transport can lead to the accumulation of damaged mitochondria, which can compromise mitochondrial quality control mechanisms, which is also noted to occur in AD [88]. 

Recently, data from the APP-PS1 mouse model showed a reduction in neuronal mitochondria density around amyloid plaques, suggesting impaired mitochondrial transport and/ or quality control in  AD [37]. 

Further, several studies indicate that axonal transport of AD-associated proteins becomes defective early in disease progression, resulting in the accumulation of toxic cargo which can elicit protein aggregation, axonal swellings, and neuronal dysfunction [36, 87]. 

The mechanisms regulating axonal transport are not completely understood but some studies suggest that it is mediated by the interaction of kinesin motor protein with the mitochondrial adaptor proteins, Miro and Milton (known as trafficking kinesin protein (TRAK) family) [89]. 

Miro is a GTPase with two Ca2+  binding EF-hand domains that is localized to the outer mitochondrial membrane (OMM) and has an essential role in Ca2+-dependent regulation of mitochondrial transport. Intriguingly, Miro1 may also serve as a cytoplasmic Ca2+ sensor and may increase mCa2+ uptake via interaction with MCU's N-terminal domain [90, 91]. 

An increase in mCa2+ has been shown to inhibit mitochondrial axonal transport and blocking mCa2+ influx into mitochondria by direct MCU inhibition enhances mitochondrial trafficking in axons [90]. 

While multiple molecular mechanisms likely contribute to AD pathogenesis, the data suggest that neuronal mCa2+ overload is a primary mediator of AD progression, causing impaired mitochondrial metabolism and ATP production, mitochondrial transport, and increased mitochondrial permeability transition pore (mPTP) opening (Fig.  1). This in turn results in loss of synaptic function, amyloid deposition, tau pathology, and cell death.

Parkinson's disease (PD)

PD is the second most common NDD affecting % of the population above 60 years of age [92]. It is clinically characterized by motor dysfunction such as tremors (involuntary shaking), bradykinesia (slowness of movements), rigidity (resistance to movement), and akinesia, as well as non-motor disturbances such as depression, anxiety, fatigue, and dementia. 

These symptoms are caused by a diminishment of the neurotransmitter dopamine due to the degeneration of dopaminergic neurons in the pars compacta of the substantia nigra in the midbrain and the deposition of intraneuronal proteinaceous inclusions known as Lewy bodies that are mainly composed of α-synuclein [93]. Most PD cases are sporadic with no known singular cause. 

Familial PD is associated with mutations in many genes including SNCA (α-synuclein) [94], PRKN (parkin) [95], PARK7  (DJ-1) [96], LRRK2 (leucine-rich repeat kinase 2) [97], and PINK1 (phosphatase and tensin homolog (PTEN)-induced kinase 1) [98]. 

Studies suggest that homozygous mutations in Parkin are the most common cause of juvenile PD, but their role in idiopathic PD is unclear. 

Mutations in Parkin are not reliably associated with Lewy body pathology. Postmortem examination of patients with Parkin mutations shows a clinical phenotype of dopaminergic neuronal loss and gliosis but lacking Lewy body pathology. 

However, this remains controversial as a few case reports demonstrate the presence of Lewy pathology in patients with Parkin mutations. Further studies are needed to define if Parkin and Lewy body pathology are in linear pathways (reviewed in [99]). 

Drug therapy for PD is limited and is primarily focused on enhancing dopamine levels via the administration of l-3,4-dihydroxyphenylalanine (L-DOPA or Levodopa), which is metabolized to dopamine after crossing the blood-brain barrier [100, 101]. 

However, this therapy is only effective in the early stages of the disease, provides symptomatic relief with many adverse side effects, and is insufficient to block the progression of PD [15, 102], suggesting a crucial need for new, effective therapies [103, 104]. 

Although the exact mechanisms of PD pathogenesis are not clear, many possible molecular events have been proposed to contribute to this process. Mitochondrial dysfunction and impaired cellular bioenergetics have emerged as likely mechanisms driving PD pathogenesis in several studies [105, 106]. Dopaminergic neurons consume 20 times more energy as compared to other neurons because of their anatomical structure (extensive long and branched axons), greater number of transmitter release sites, and their pacemaking activity [107]. 

The high-energetic demand of dopaminergic neurons makes them more susceptible to mitochondrial dysfunction and eventually to cell death in comparison to other neuronal cells [108, 109]. Defects in mitochondrial respiration are supported by findings of reduced glucose utilization in PD patients [110], as well as reduced pyruvate oxidation in fibroblasts derived from PD patients [111], which suggest reduced acetyl-CoA entry into the TCA cycle. The first study showing that defects in mitochondrial respiration may be causal in PD came in the early 1980s. In this study, experimental inhibition of complex I (NADH-ubiquinone reductase) of the ETC was sufficient to cause parkinsonism [112, 113]. 

This is consistently supported by observations of a profound reduction in ETC activity, mostly complex I, in the substantia nigra, platelets, and skeletal muscle of PD patients [114]. Furthermore, inhibitors of complex I, such as MPP+ (1-methyl-4-phenylpyridinium), 6-hydroxydopamine, rotenone, and annonacin all elicit PD-like phenotypes, suggesting that mitochondrial dysfunction is sufficient to promote neuronal dysfunction in PD [115–117]. 

Complex I is a key entry point for electrons into the respiratory chain and is responsible for 40% of mitochondrial ATP production [118, 119]. In addition to complex I, a reduction in complex II and III activity and the mitochondrial DNA (mtDNA) transcription factor, TFAM, has also been reported in PD patients [120–122]. 

Reduced ETC capacity in PD may cause a significant reduction in ATP [123] resulting in a cellular energy crisis that can impact various processes including (1) ATP-dependent proton pumps that drive vesicular accumulation of dopamine [124, 125]; (2) axonal transport of cargo [126]; (3) mitochondrial dynamics (fusion, fission, turnover, biogenesis, and transport) [127, 128]; and (4) ATP-dependent protein degradation systems (e.g. ubiquitin-proteasome and autophagy) [129, 130]. 

In addition, complex I and III deficiency in PD is linked with increased production of free radicals that further impair mitochondria function, drive protein aggregation, and culminate in cell death [131–133]. 

Dopamine is very unstable and sequestered inside synaptic vesicles via the ATP-dependent vesicular monoamine transporter. 

If not sequestered, it is metabolized by monoamine oxidase to the toxic dopamine metabolite 3,4 dihydroxyphenylacetaldehyde, which contributes to oxidative stress, mPTP opening, and dopaminergic neuronal cell death [134]. 

Over the past decades, many PD-associated genetic mutations have been found to elicit changes in mitochondrial function and metabolism, supporting the notion that mitochondrial dysfunction is implicated in neuronal cell loss associated with familial PD and vice versa [98]. Mutant α-synuclein localizes to the inner mitochondrial membrane [135] inhibits complex I activity, and promotes oxidative stress [136]. 

The interaction of α-synuclein with mitochondria can result in cytochrome c release, increased mCa2+ levels, changes in mitochondrial morphology, and a decline in mitochondrial respiration. 

α-synuclein-mitochondrial interplay may also inhibit autophagic clearance and increase its aggregation propensity (reviewed in [137]). A recent study suggested that mitochondrial impairments occur with Lewy body formation [138]. 

Furthermore, loss of function mutations in DJ-1 caused impairments in OxPhos, and complex I assembly resulting in decreased ATP production, oxidative stress, and increased glycolysis [139, 140]. 

These findings raise the possibility that mitochondrial dysfunction is causal in maladaptive protein aggregation. Furthermore, Parkin, as an E3 ubiquitin ligase, is directly involved in the proteasomal degradation of protein aggregates. 

It localizes to mitochondria and prevents cytochrome c release, mitochondrial swelling, and the accumulation of α-synuclein, which may protect dopaminergic neurons from mitochondrial and neuronal dysfunction [141–143]. 

Parkin and PINK1 are required for mitochondrial quality control [144, 145]; thus, loss of Parkin/PINK1 function is hypothesized to cause the accumulation of dysfunctional mitochondria that impair neuronal function. 

Previous work revealed that PINK1 deficient neurons display reduced NCLX-dependent mCa2+ reflux resulting in matrix Ca2+ overload and subsequent mPTP opening, mitochondrial oxidative stress, lower Δψm, and diminished OxPhos [146]. 

Furthermore, fibroblasts derived from patients with PINK1 mutations also exhibited impaired mitochondrial metabolism, low Δψm, and low respiration, which was linked to reduced substrate availability [147]. 

In addition, the activation of NCLX via protein kinase A (PKA)-dependent phosphorylation of serine 258, a putative NCLX regulatory site, increases mCa2+ reflux and protects PINK-1 deficient neurons from mitochondrial dysfunction and cell death [148]. 

This paradigm fits with previous reports where mCa2+ overload caused by increased mCa2+ uptake (via ERK1/2-dependent upregulation of MCU) caused dendritic degeneration in a late-onset familial PD model (mutation in LeucineRich Repeat Kinase 2) [149], and a report of MCU overexpression eliciting excitotoxic cell death [78]. 

Along the same line, inhibition of  MCU is protective in zebrafish models of PD [150, 151]. These findings suggest that mCa2+ overload is a contributor to PD progression.

In summary, increasing evidence supports the centrality of impaired mitochondrial function and metabolism in both sporadic and familial PD, resulting in oxidative stress, ETC dysfunction, defective mitochondrial quality control, protein aggregation, progressive cellular dysfunction, and neurodegeneration.

Huntington's disease (HD)

HD is an autosomal-dominant neurodegenerative disease resulting from an expansion of cytosine–adenine–guanine (CAG) repeats (>35 bp) within the coding sequence of the huntingtin gene (HTT). 

Mutant huntingtin protein (mHtt) is prone to proteolytic cleavage, misfolding, and aggregation. Clinically, HD is characterized by progressive motor, cognitive, and behavioral dysfunction largely due to the loss of γ-aminobutyric acid (GABAergic) medium spiny neurons in the striatum [152]. 

The energy impairment hypothesis of HD was first proposed in the early 1980s from clinical observations, which revealed defects in brain glucose utilization and weight loss in HD patients  [153, 154]. 

Consistently, compelling evidence from PET studies suggests decreased glucose utilization in HD brains [155, 156], suggesting a defect in metabolism. In addition, compared to a control population, presymptomatic HD children, with no manifest symptoms, revealed a lower body mass index suggesting energy dysregulation and impairments in anabolic growth [157]. 

In HD patients, many key enzymes of the TCA cycle, ETC display reduced expression, including PDH, SDH, complex II, III, and IV [158]. In addition, HD patients increase lactate production in the pre-symptomatic phase of HD, indicating a possible reduction in oxidative mitochondrial metabolism and metabolic shift from OxPhos to glycolysis [159–162]. 

Irreversible inhibition of SDH by chronic administration of 3-nitro propionic acid in both rodents and non-human primates elicited regional lesions in the striatum accompanied by HD-like pathology [163–165]. 

These results suggest that defects in key TCA cycle enzymes are sufficient to drive HD pathology. 

Furthermore, treatment of an HD mouse model with coenzyme Q and creatine for energy supplementation resulted in increased longevity and improved motor function [166, 167], suggesting that improving mitochondrial function and cellular bioenergetics is a viable therapeutic approach to treating HD.

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