Reappraisal Of Metabolic Dysfunction in Neurodegeneration: Focus On Mitochondrial Function And Calcium Signaling Part 1
Aug 28, 2024
Abstract
The cellular and molecular mechanisms that drive neurodegeneration remain poorly defined. Recent clinical trial failures, difficult diagnoses, uncertain etiology, and lack of curative therapies prompted us to re-examine other hypotheses of neurodegenerative pathogenesis.
Neurodegenerative diseases are difficult to prevent, such as Alzheimer's, Parkinson's, and Alzheimer's. These diseases can seriously affect patients' memory and quality of life.
Although these diseases cannot be prevented, we can take steps to slow their development and impact. Some studies have shown that keeping our bodies and brains healthy can help us better fight these diseases and protect our memory.
Relaxation techniques that emphasize focus and deep thinking, such as meditation and yoga, may help improve memory and enhance brain health. In addition, socializing, participating in group activities, reading, and learning new knowledge can also help us keep our brains active and strong.
Maintaining healthy lifestyle habits, such as a balanced diet, adequate sleep, proper exercise, and avoiding drugs and alcohol, can also help us keep our bodies healthy. A healthy body will better perfuse the brain, thereby effectively fighting neurodegenerative diseases.
Although these measures cannot guarantee that we are immune to neurodegenerative diseases, they can help us improve our memory, protect brain health, and give us more confidence and courage when facing these challenges. In any case, we should have a positive attitude and do our best to maintain a healthy lifestyle and protect our brains.
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Recent reports establish that mitochondrial and calcium dysregulation occur early in many neurodegenerative diseases (NDDs), including Alzheimer's disease, Parkinson's disease, Huntington's disease, and others. However, causal molecular evidence of mitochondrial and metabolic contributions to pathogenesis remains insufficient.
Here we summarize the data supporting the hypothesis that mitochondrial and metabolic dysfunction result from diverse etiologies of neuropathology.
We provide a current and comprehensive review of the literature and interpret that defective mitochondrial metabolism is upstream and primary to protein aggregation and other dogmatic hypotheses of NDDs.
Finally, we identify gaps in knowledge and propose therapeutic modulation of mCa2+ exchange and mitochondrial function to alleviate metabolic impairments and treat NDDs.
Keywords: Mitochondria, Metabolism, Calcium, Neurodegeneration, Alzheimer's disease, Parkinson's disease, Huntington's disease.
Introduction
The brain consumes 20% of the body's ATP at rest, although it accounts for only 2% of body mass [1]. The high-energy requirements of the brain support neurotransmission, action potential firing, synapse development, maintenance of brain cells, neuronal plasticity, and cellular activities required for learning and memory [2, 3]. In neurons, most of the energy is consumed for synaptic transmission.
Action potential signaling represents the second-largest metabolic need, and it is estimated that 400–800 million ATP molecules are used to reestablish the electrochemical gradient (Na+ out, K+ in, at the plasma membrane) after the production of the single action potential [4].
The energetic demand of neurons results in a substantial dependence on mitochondria for ATP production through oxidative phosphorylation (OxPhos) [4]. Any dysfunction in mitochondria can lessen the energetic capacity of OxPhos and may elicit a metabolic switch from OxPhos to glycolysis (Warburglike effect) as a compensatory attempt to maintain cellular ATP in the context of neurodegenerative stress [5, 6].
However, a long-term OxPhos-to-glycolysis shift can result in a bioenergetic crisis and make neurons more vulnerable to oxidative stress and neuronal cell death [7, 8].
Neurodegenerative diseases (NDDs) are characterized by numerous cellular features, including the loss of neurons, neuronal dysfunction in specific brain regions, aggregation of distinct protein(s), impaired protein clearance, mitochondrial dysfunction, oxidative stress, neuroinflammation, axonal transport defects, and cell death.
The myriad of cellular pathologies suggests that there are common/central molecular mechanisms driving NDDs [9, 10]. In addition to ATP production, the mitochondrion is an epicenter of many metabolic pathways and important cellular functions, including the fine-tuning of intracellular calcium (i Ca2+) signaling, regulation of cell death, lipid synthesis, ROS signaling, and cellular quality control [11].
Disruption in mitochondrial function and metabolism appears to underlie several NDDs such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and others [12, 13].
At present, most therapies for NDDs provide only symptomatic relief, and there remain no drugs to inhibit neurodegeneration [14–16]. Mitochondrial alterations/impaired brain energetics are thought to present in the asymptomatic stage of disease before the onset of clinical symptoms [14, 17, 18]. This supports the notion that mitochondrial metabolic defects may be drivers or even initiators of the neurodegenerative process.
In addition, several therapeutics that improve mitochondrial function have been reported to be efficacious in NDD models [19–21].
Mitochondrial calcium (mCa2+) is a critical regulator of mitochondrial function. In the matrix, mCa2+ tightly regulates TCA cycle activity and augments metabolic output. However, an excess of mCa2+ can impair mitochondrial respiration, enhance reactive oxygen species (ROS) production, and activate cell death [22].
Here, we hypothesize that dysfunction in mCa2+ is an early common cellular event that impairs mitochondrial metabolism and drives and exacerbates neuropathology.
Defining the molecular basis of mitochondrial function and metabolism in NDDs will help define novel cellular events and pathways and their temporal occurrence in NDD progression to identify new therapeutic targets for various neurological conditions.
Here, we review recent advancements in our understanding of the essential role of mitochondrial metabolism and discuss how impaired mCa2+ signaling may be causal and central in neurodegeneration.
Evidence for impaired mitochondrial metabolism in NDDs
Strategies to combat NDDs have generally been unsuccessful and are focused on reducing symptoms and disease modification. Both clinical and experimental studies suggest that impaired energy metabolism correlates with various neurological defects, highlighting new therapeutic opportunities [14]. Here we outline various mitochondrial metabolic defects that are strongly linked to the progression of neurodegeneration.
Alzheimer's disease (AD) AD is the most common form of dementia and is characterized by irreversible memory loss due to neuronal dysfunction, dysconnectivity, and cell death.
Familial AD (FAD) is caused by pathogenic mutations in amyloid precursor protein (APP) or presenilin (PS1 and PS2) that lead to overproduction, improper cleavage, and the accumulation of amyloid-beta (Aβ).
Prognostic disease phenotypes are associated with the formation of Aβ plaques, neurofibrillary tangles (NFTs, consisting of the microtubule protein tau), synaptic failure, reduced synthesis of the neurotransmitter acetylcholine, and chronic inflammation [9].
Most therapeutic strategies have been focused on Aβ metabolism and clearance due to extensive preclinical and clinical data in support of a causal role in AD progression [23, 24].
According to the "amyloid cascade hypothesis," Aβ aggregation can initiate a series of events, including tau pathology, oxidative stress, inflammation, neuronal calcium (Ca2+) dysregulation, and metabolic alterations, which culminate in neuronal cell loss and AD pathogenesis [25]. However, this hypothesis does not fully explain the etiology of sporadic forms of AD (SAD) that account for 90–95% of AD-associated dementia.
An alternative hypothesis is that the microtubule-associated protein tau becomes hyperphosphorylated, resulting in axonal transport defects of organelles (including mitochondria), synaptic dysfunction, and cell death [26]. In cortical brain tissue from AD patients and mouse models, tau is reported to interact with mitochondrial transporters and complexes, resulting in mitochondrial dysfunction and AD pathology [27, 28].
However, there appears to be a limited correlation between the severity of cognitive decline and amyloid or tau plaque formation [29, 30], suggesting Aβ/tau metabolism and processing may not be the cause, or at least the singular cause, of disease. Consistent with previous studies, RNA-sequencing data from AD patients also suggest that Aβ and tau accumulation may not be mediators of the disease [31, 32].
Also, clinical trials of therapies targeting Aβ/tau production, metabolism, and clearance have universally shown little efficacy making it likely that other proximal mechanisms of AD pathogenesis exist [33, 34]. Mitochondrial dysfunction appears to be a primary occurrence in AD that precedes Aβ deposition, synaptic degeneration, and NFT formation.
In support of this concept, cytoplasmic hybrid cells (cybrids) generated from platelet mitochondria of SAD patients were reported to have a deficiency in complex I and complex IV of the electron transport chain (ETC), reduced mitochondrial membrane potential (Δψm), altered mitochondrial morphology, increased Aβ generation and tau oligomerization (reviewed in [35]).
Transmission electron microscopy (TEM) showed smaller mitochondria with altered cristae structure and a decrease in mitochondrial content both in AD mice and patients [36–38].
Furthermore, fibroblasts derived from SAD patients also showed impaired mitochondrial dynamics, bioenergetics, and Ca2+ dysregulation [17, 39]. This change in mitochondria morphology in AD may be due to a shift in the mitochondrial fission/fusion balance and a decrease in biogenesis [40]. Importantly, experimental evidence suggests that bioenergetic alterations in AD precede the formation of Aβ plaques [41].
Data supporting metabolic deficits in AD were first published in the early 1980s from 2-[18F] fuoro2-deoxy-D-glucose (FDG) positron emission tomography (PET) studies, which showed reduced glucose metabolism in the parietal, temporal, and frontal cortex of AD patients [42–44].
Postmortem brain tissue isolated from AD patients displays reduced mitochondrial metabolic enzyme activity for pyruvate dehydrogenase (PDH) [45, 46], alpha-ketoglutarate dehydrogenase (α-KGDH) [46], isocitrate dehydrogenase (ICDH) [47], and complex IV or cytochrome-c-oxidase (COX) [48–50]. In addition, succinate dehydrogenase (SDH) and malate dehydrogenase (MDH) activity are increased in AD patient's brains [51].
Microarray data [52] and bioinformatics analysis of four transcriptome datasets [53] suggest a significant downregulation in nuclear-encoded OxPhos genes in the hippocampus of AD patients.
More recent data confirm impaired ATP synthase activity due to loss of the oligomycin-sensitive conferring protein subunit in the brain of FAD and SAD patients [54]. Diminished PDH function, as noted in AD, limits the shuttling of pyruvate into the TCA cycle, causing pyruvate accumulation and favoring anaerobic metabolism.
Anaerobic metabolism leads to the production of lactic acid and further reduces acetyl-CoA availability, which subsequently decreases OxPhos. These observations suggest a metabolic shift from OxPhos to glycolysis may occur with AD progression.
This shift is perhaps a compensatory response to enhance energy production through glycolysis, which is noteworthy in the context of mitochondrial dysfunction [5, 6]. Interestingly, PDH, α-KGDH, and ICDH activity are all reported to be calcium-controlled, suggesting a clear link between mCa2+ levels and AD pathogenesis, which will be discussed in the upcoming section.
A recent study also indicates that reduced mitochondrial pyruvate uptake in FAD-PS2-expressing cells may elicit impairments in bioenergetics and mitochondrial ATP synthesis [13].
The mechanism for defective mitochondrial pyruvate fux is associated with the hyper-activation of glycogen-synthase-kinase-3β (GSK3β), which decreases hexokinase 1 association with mitochondria and destabilizes the mitochondrial pyruvate carrier complexes [13].
Similarly, α-KGDH is sensitive to oxidative stress, and its reduced activity in PS1 mutant (M146L) fibroblasts suggests a possible mechanism for ROS-dependent metabolic deficiencies [18, 55]. Oxidative stress, as seen in AD brains [56], is reported to increase the expression of SDHA (one of the four nuclear-encoded subunits of complex II, SDH) [57, 58], and the activity of MDH [59].
In summation, alterations in key metabolic enzymes may compromise the neurons' ability to generate ATP via OxPhos and be an early driver of cellular stress in AD.
Beyond energetic compromise, diminished acetyl-CoA supply caused either by a reduction in glucose metabolism or by reduced PDH activity impairs the synthesis of the neurotransmitter acetylcholine (ACh).
ACh is generated from choline and acetyl-CoA by choline acetyltransferase. After synthesis, ACh is transported via an ATP-consuming process and stored in synaptic vesicles [60].
The loss of ACh synthesis in AD results in defective cholinergic neurotransmission [61, 62]. This provides another tangible link between energetic compromise and neuronal dysfunction in AD.
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