Sher Zaman Safi 
Department of Biochemistry, Faculty of Medicine, MAHSA University, Jenjarom, Selangor, Malaysiav
Correspondence to: dr.szsafi@gmail.com
Additional information
- Ethical approval: N/a
- Consent: N/a
- Funding: No industry funding
- Conflicts of interest: N/a
- Author contribution: Sher Zaman Safi – Conceptualization, Writing – original draft, review and editing
- Guarantor: Sher Zaman Safi
- Provenance and peer-review:
Commissioned and externally peer-reviewed - Data availability statement: N/a
Keywords: Cellular metabolism, Electron transport chain, Mitochondrial dysfunction, Neurodegenerative diseases, Oxidative stress.
Peer Review
Received: 31 October 2024
Revised: 6 November 2024
Accepted: 7 November 2024
Published: 19 November 2024
Abstract
Neurodegenerative diseases are characterized by the progressive loss of neuronal function and structure and are accompanied by cognitive decline, motor impairment, and behavioral changes. Mitochondrial dysfunctions include oxidative stress, energy deficiency, programmed cell death, and calcium dysregulation. Mitochondria are a fundamental energy-generating structure of eukaryotic cells. During ATP synthesis via energy transduction, producing reactive oxygen species from free radicals can damage various molecules, leading to mitochondrial impairment. Parkinson’s disease, Alzheimer’s disease (AD), Huntington’s disease, and amyotrophic lateral sclerosis (ALS) are common chronic neurodegenerative disorders in older adults, usually linked with dysfunction in the mitochondrial electron transport chain complexes. In healthy cells characterized by unceasing division and fusion, the process of the biogenesis of mitochondria is tightly bound to the nuclear and mitochondrial DNA.
In unhealthy cells, however, division (fission) leads to the fragmentation of the mitochondrial network following brain injury. AD is associated with cytochrome oxidase deficiency and deregulation of metabolic enzymes, observed in nonneural cells such as fibroblasts, platelets, and peripheral blood cells. Friedreich’s ataxia results from an expanded GAA repeat that disrupts the function of frataxin, leading to iron accumulation and oxidative damage. Familial ALS is linked to point mutations in superoxide dismutase, which may increase free radical production, exacerbating mitochondrial dysfunction. This review aims to explore the role of mitochondrial dysfunction in cellular metabolism and its implications for the progression of degenerative diseases. This article seeks to analyze how disruptions in mitochondrial function contribute to disease pathology, focusing on the mechanisms by which mitochondrial deficits impact metabolic processes across various degenerative conditions.
Introduction
Mitochondria are highly adaptable and dynamic organelles essential for cellular metabolism, stress responses, and maintaining homeostasis. They serve as the primary point for various molecular and biochemical processes, including reactive oxygen species (ROS), adenosine triphosphate (ATP) production, fatty acid synthesis, oxidative phosphorylation (OXPHOS), thermogenesis, and calcium (Ca²+) homeostasis.1,2 Mitochondria are also vital for regulating numerous cellular functions, including glutamate and urea metabolism, antioxidant defense, and apoptosis pathways. They serve as a significant source of ROS generated by the electron transport chain (ETC). However, mitochondria are susceptible to oxidative damage, which can result in mitochondrial dysfunction and subsequent tissue injury.3–5 Mitochondrial dysfunction can be affected by various factors, including lifestyle choices, genetic mutations, aging, and infections.6 Unhealthy diets, lack of exercise, and exposure to toxins can exacerbate mitochondrial impairment. One of the primary consequences of mitochondrial dysfunction is the impaired production of ATP, leading to energy deficits that can significantly disrupt cellular metabolism. Genetic mutations, whether inherited or acquired, can directly disrupt mitochondrial function and energy production. Aging is associated with a decline in mitochondrial efficiency and an increase in oxidative stress, while infections can provoke inflammatory responses that further damage mitochondrial integrity, compounding the effects of these other risk factors (Figure 1).7–11
Under normal circumstances, less than 2% of oxygen leaks from the mitochondrial ETC.12 However, it is well recognized that damaged mitochondria can generate significantly higher levels of ROS under various pathological conditions.13 Mitochondria are also known to generate reactive nitrogen species (RNS), including nitric oxide (NO), through the action of NOS present in these organelles.14,15 The accumulation of ROS and RNS alters several key processes, leading to the inactivation of several proteins, cell death, and mitochondrial dysfunction.16–18 These alterations consequently drive the initiation and progression of numerous pathological conditions, including neurodegenerative disorders like Parkinson’s disease (PD), Alzheimer’s disease (AD), Huntington’s disease (HD), traumatic brain injury, ischemia-reperfusion injuries in the brain, and dementia linked to alcohol use.19,20 This review aims to examine the impact of mitochondrial dysfunction on cellular metabolism and its implications for the pathogenesis of degenerative diseases. By elucidating the multifaceted interactions between mitochondrial health and metabolic processes, we aim to identify potential therapeutic strategies that could mitigate the detrimental effects of mitochondrial dysfunction and enhance the resilience of cells in the face of various pathological challenges.
Methodology
Identification: A total of 182 articles were initially identified from comprehensive database searches, including PubMed, Web of Science, ScienceDirect, Medline, EMBASE, Google Scholar, and BioMed Central. The search strategy employed relevant keywords such as “mitochondrial dysfunction,” “cellular metabolism,” “oxidative stress,” “energy homeostasis,” and “degenerative diseases,” combined in various configurations like “mitochondrial dysfunction and degenerative diseases” and “metabolic dysfunction in neurodegeneration.” After the initial screening, 23 duplicate records were removed, leaving 159 unique articles for further examination.
Screening: Once the removal of duplicate articles was completed, a preliminary review of the 159 articles was conducted. Titles and abstracts were carefully assessed to ensure relevance to the topic of mitochondrial dysfunction in degenerative diseases. This resulted in the exclusion of 17 articles that lacked direct relevance, reducing the pool of articles to 142. A further 31 articles were excluded based on their broad relevance to the topic, leaving a total of 111 articles.
Eligibility: For eligibility assessment, full texts of the remaining 111 articles were reviewed to determine their eligibility. Articles that were not in English or did not exactly describe the topic “Mitochondrial dysfunction and its impact on cellular metabolism in degenerative diseases” were excluded. A total of 14 studies were excluded as they were not directly related to the topic. Consequently, 97 studies met the criteria for further evaluation.
Final Selection: In the final phase, four more studies were excluded for failing to meet quality standards, as they were not published in reputable, peer-reviewed journals. Ultimately, 93 articles were selected for inclusion in this review, each contributing valuable insights into mitochondrial dysfunction, metabolic dysregulation, and their implications for therapeutic approaches in degenerative diseases (Figure 2).
Inclusion and Exclusion Criteria: The existing literature related to mitochondrial dysfunction and its impact on cellular metabolism in degenerative diseases was searched. No restriction was set on publication years; however, this article includes studies published between 1988 and 2023. Articles were evaluated based on the criteria listed below in Table 1.
| Table 1: Exclusion and Inclusion Criteria. | ||
| NO | Exclusion and Inclusion Criteria | |
| Inclusion Criteria | Exclusion Criteria | |
| 1 | Articles authored in the English language | Articles written in languages other than English |
| 2 | Articles focused on mitochondrial dysfunction, cellular metabolism, and degenerative diseases | Articles with incomplete or insufficient data |
| 3 | Articles discussing the molecular mechanisms of mitochondrial dysfunction, cellular metabolism, and degenerative diseases | Correspondence and commentaries |
| 4 | Articles describing the risk factors associated with these conditions | Articles and materials from unauthentic resources such as journals with no indexing |
Mitochondrial Dysfunction and Cellular Metabolism in Degenerative Diseases
Reduced mitochondrial mobility and increased mitochondrial fission are two pathogenic alterations in the process of mitochondrial fusion that have a positive correlation with mitochondrial pathology and aging-related cell death. The mitochondrial ETC complex has been linked to dysfunction in a number of the most prevalent chronic neurodegenerative diseases affecting the elderly, including PD, HD, amyotrophic lateral sclerosis, and AD. Mitochondrial trafficking refers to the movement of dynamic organelles called mitochondria on cytoskeletal proteins. They fragment, swell, lengthen, and are constantly and systematically recycled (by mitophagy or vesicle formation) as well as fuse and divide (fission is controlled by the proteins fission 1 and Drp1). Mitochondrial elongation results from imbalanced fusion, while tiny mitochondria and excessive fragmentation from unbalanced fission both affect mitochondrial function. It has been demonstrated that both the distribution of organelles in neurons and the function of mitochondria depend on the exchange of their contents. The cerebellum needs mitochondrial fusion, specifically that mediated by Mfn2, to develop and function properly.21 Upregulation of mitochondrial genes and elevated levels of mitochondrial DNA (mtDNA) correlate well with increased biogenesis. Some of the genes that remarkably relate to the profile of mitochondria along with their function are PGC-1a, TFAM, NRF1/2, and TFB1M (Figure 3).22,23
Parkinson’s Disease
PD is a motor system disorder of the brain, bradykinesia or hypokinesia, resting tremor, postural instability, and rigidity.24 PD also affects non-motor symptoms, which include autonomic dysfunction, dementia, depression, and insomnia. Although some of these symptoms may be present and constant with the motor disturbances, these symptoms are most often seen before such manifestations though the general rule may not apply in all cases. The degeneration is actually in the dopaminergic (DA) system, leading to the motor symptom. PD occurs through several processes at different levels. Some issues related to mitochondrial dysfunction are also common in PD.25 Reduced glutathione has been reported to lead to the buildup of hydroxyl as well as superoxide radicals the same as the PD patients in their brains. These factors may also contribute to elevated oxidative damage, along with the previously discussed mitochondrial ROS. They include the presence of iron and an augmentation in the number of lipid peroxidation events.26–28 However, new observations have proved that alpha-synuclein oligomers are toxic directly to the mitochondria.29 Studies have demonstrated that the neurotoxic effects of alpha-synuclein are linked to increased ROS production and the disruption of mitochondrial membrane integrity (Figure 3).30
A decrease in the synthesis of mitochondrial complex I enzyme has been reported as one of the potential mechanisms by which mitochondrial dysfunction may lead to the development of PD. Currently, the biomarkers used for screening PD include blood markers such as α-synuclein and its isoforms, genetic markers, and the measurement of mitochondrial complex I activity. Though PD is understood to have its genesis in mitochondrial dysfunction, there is still the potential to identify other biomarkers which will allow early diagnosis.31 According to a study, 6-OHDA, a structural analog of dopamine, induces motor deficits in mice and rats and is associated with mitochondrial-related neuronal death in vitro. It also carries an extra hydroxyl group which is linked with oxidative stress in DA neurons. Likewise, the Nrf2/Keap1 signaling pathway seems to be strongly associated with the aberrant thermal profile, elevated oxidative stress, and aberrant dopamine-dependent behavior.33–36 Mitochondrial dysfunction remains central to the pathology of PD, underscoring the need for continued exploration of mitochondrial markers. These insights emphasize the complex interplay between oxidative stress, neuronal death, and molecular pathways that collectively shape the progression of PD.
Alzheimer’s Disease
AD is characterized by chronic neuronal degeneration and biochemical changes due to impaired mitochondria.37 Synaptic contacts identified with high density in AD are associated with β-amyloid plaques that aggregate in mitochondria. It has been reported that it reduces the normal anterograde and retrograde transport of mitochondria within the hippocampal neurons and synapse degradation characteristic of AD. A study revealed that exposure to β-amyloid reduced the number of motile mitochondria in mouse hippocampal neurons and altered mitochondrial distribution, with fewer mitochondria moving in the anterograde direction. This shift contributed to synaptic breakdown and ATP imbalance, hallmarks of the disease.38 AD patients have hypometabolism of energy in the brain caused by the reduced microvascular density in some parts of the brain, which could lead to ischemic states. Thus, reduced blood flow and oxygen availability lead to decreased ATP production, which leads to oxidation stress, Na+K+ATPase dysfunction, disruption of signal transduction, neurotransmitter dysfunction, and impaired APP cleavage generating increased BACE levels that promote Aβ overproduction. In addition, mutated proteins are formed by poor folding, dismantling, and cutting out of protein molecules resulting from impaired energy metabolism, which in turn affects other cellular formations. Tau hyperphosphorylation from the aberrant metabolism will also lead to microtubule injury. The cortical and hippocampus regions of the brain are particularly susceptible to energy hypometabolism and related metabolic alterations that lead to memory impairments.39 An additional factor contributing to brain hypometabolism in AD is the high-energy demand of hyperactive microglia, or the highly activated immune system within the brain, which restricts the energy supply available to neurons.40
Impaired glucose metabolism results in the loss of synaptic signaling, transmembrane ion transport, and vesicle recycling in the brain.41,42 This also causes hyperexcitability, an imbalance between excitation and inhibition, and functional impairment of cortical neurons, all of which worsen the brain’s energy efficiency.40 AD has a long-standing correlation with two primary pathological features: the buildup of intracellular fibrillary tangles containing neurite tau and extracellular plaques containing β-amyloid (Aβ) that originate from the amyloidogenic pathway.43 The deregulation of the metabolic enzymes has been reported in nonneural cell types such as fibroblasts, platelets, and peripheral blood cells derived from AD patients.44 According to the studies by Gabuzda et al., the fibroblast-like cells’ metabolic state is a critical factor in the synthesis of amyloidogenic derivatives.45 Leuner’s study proved that these ROS drive the processing of Aβ peptide (AβPP) toward Aβ both in vitro and in vivo.46 However, it has been proved that modifications of energy metabolism and mitochondrial dysfunction can prompt the formation of tau tangles and Aβ plaques. Long-term electron microscopy research in AD brains showed aberrant mitochondrial ultrastructure.47,48 Apoptotic markers such as caspase 3, cytochrome C, and C terminal short-tailed Aβ 1–40 variant (Aβ40) and Aβ42 were upregulated in experiments where platelet-derived cytoplasm from AD patients was transplanted into human cells.49 Another study showed that apoptotic pathways, oxidative stress, cytochrome c release from mitochondrial intermembrane/intercristae gaps, abrupt increases in intracellular Ca2+ concentrations, and the acquisition of mt-DNA mutations occur before mitophagy.
Their long-term dysregulation, however, is associated with the development of mitochondrial malfunction and the eventual death of neurons.50 Mitophagy (Figure 3), also known as mitochondrial autophagy, is essential in response to numerous pathogenic stimuli, including Aβ and p-tau in AD. It is regulated by the Parkin–PINK1-mediated receptor-mediated mitophagy. In receptor-mediated mitophagy, the PINK1 protein accumulates on the outer mitochondrial membrane, facilitating Parkin recruitment to initiate the mitophagy process. Alongside PINK1 and Parkin, other key proteins—such as NIX/BNIP3L, FUNDC1, and LC3—play essential roles by engaging with LC3 and enhancing the mitophagy pathway, ensuring the targeted removal of damaged mitochondria. These proteins drive PINK1/Parkin-independent mitophagy under hypoxic settings by facilitating the autophagosome’s engulfment of damaged mitochondria.51
Amyotrophic Lateral Sclerosis
ALS, a mechanical ventricular dysfunction, occurs progressively in adults and ends up in paralysis to the point of death. Skeletal muscle denervation and degeneration resulted from the loss of motor neurons in the spinal cord and brain in both human and rodent models. Recent research evidence has proven that impaired expression of mitochondrial Ca2+ capacity, changes in the distribution of axonal mitochondria along with dimorphism, higher levels of ROS generation in the CNS, muscles of ALS patients, and compromised mitochondrial respiratory and ATP production have significant roles in the toxicity of mitochondria in ALS. In ALS patients, mitochondrial dysfunction in skeletal muscle is characterized by reduced protein levels of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) and PGC-1 beta (PGC-1β), Mitofusin-1 (Mfn1), Mitofusin-2 (Mfn2), Estrogen- Related Receptor Alpha (ERRα), and nuclear respiratory factor-1 (NRF). Additionally, there is an upregulation in mRNA levels of various microRNAs that may play a role in neuromuscular junction maintenance and skeletal muscle regeneration. This means that degraded mitochondrial function in skeletal muscles is a significant cause of ALS.52
Additionally, a recommendation was made that it is through this specific signaling route, PPAR-c, that neuroinflammation, a symptom of ALS, may be initiated. Higher levels of complex I activity in postmortem brain tissue may be a compensative response to pathologically decreased expression of the mtDNA-encoded enzyme, complex IV, in certain forms of ALS. But in postmortem spinal cord tissue of fALS and sALS cases, the activities of complexes I + III, II + III, and IV are also decreased in a manner proportional to the decrease in citrate synthase activity. A reduction in mtDNA damage or the selective loss of certain mitochondria in the spinal cord results in an overall decrease in mitochondrial content. More than 130 well-characterized isoforms of the Cu/Zn superoxide dismutase (SOD1) gene have been linked to ALS. While the molecular pathogenic mechanisms involve mutant SOD1 (mSOD1)-induced mitochondrial dysfunction, recent studies reveal that ALS-associated SOD1 mutations selectively target mitochondria, leading to impaired respiratory function.
Besides structural and functional changes in the mitochondria of muscle, experimental evidence indicated that muscle atrophy due to denervation is considered one of the early features of ALS.53 The loss of PGC-1a regulatory networks that are involved in mitochondrial adaptations is associated with mitochondrial dysfunction of skeletal muscles in ALS patients. Survival was not advanced; drugs that enhance PGC-1a in skeletal muscle are a good approach for supporting muscles as ALS progresses. It has recently been proven that the same transgenic mice model of ALS showed that SIRT1 activation enhances motor neuron survival through the activation of PGC-1a.54 Furthermore, crosstalk between PPARs, which are an identified receptor in ALS, has displayed neuroinflammation signaling and may be a new therapeutic target for ALS.
Huntington’s Disease
The huntingtin (Htt) gene contains cytosine–adenine–guanine (CAG) triplet repeats, encoding polyglutamine stretches that cause HD, a hereditary neurodegenerative disorder. This expansion results in the accumulation of insoluble, polyglutamine-containing Htt protein within neurons, leading to cellular dysfunction and disease progression. The signs of pathophysiology in HD are poorly understood but associated with mitochondrial abnormalities.55–57 Cui and his colleagues identified two aspects of how HD advances when PGC-1a is genetically erased: striatal neurodegeneration and motor coordination. They also stated that patients with HD have lower values of mitochondrial ATP, as well as ETC activity.58 Biochemical evaluation of the OXPHOS complexes including complexes II, III, and IV expressed in mitochondria of striatal neurons have further shown a decline in their activities in late onset. Furthermore, studies have reported reduced activity of mitochondrial complexes I, II, III, and IV in the neostriatum of patients with HD.59–61
HD has lower mitochondrial ATP levels and ETC activity.62 Another cause of mitochondrial dysfunction in the brains of HD patients may also be due to the toxic effects arising from the mutant Htt which brings about those changes in the activity of mitochondrial complex.63 According to the primary theory on postmortem anomalies in the mitochondrial respiratory chain following a patient’s demise, the toxic manifestation of mHtt is either the primary or secondary cause of these pathologies. On the other hand, in HD patients, mHtt production selectively reduces complex III activity and enhances aggregated/ misfolded Htt protein generation by decreasing the activity of the proteasome. Therefore, the proteasome, misfolded/aggregated HTT protein, and mitochondrial complex III provide feedback systems suggesting that activating this complex III, in particular, will arrest, or perhaps even reverse, the pathology of HD.62,63 The harmful consequences of mutant Htt, which produce those alterations in mitochondrial complex activities, are another possible reason for mitochondrial dysfunction in HD brains.63 Kim et al. demonstrated a significant, pathology-dependent reduction in mitochondrial numbers within striatal spiny neurons, which corresponded closely with decreased levels of TFAM and PGC-1α.64
In addition, it has been established that both myoblast cultures and muscle biopsies of HD patients have low levels of expression of TFAM and PGC-1a.61 These outcomes are quite beneficial in pinpointing the reduced expression of PGC-1a in the development of HD.64 A previous study reported that the pathology of HD is greatly precipitated by the dysfunction of mitochondria in the mHtt-expressing cells and that activation of PPAR-c receptors may counteract this situation.55 Similar findings have been demonstrated in mHtt striatal cells by authors who have shown that PPAR-c agonists decrease mitochondrial impairment and protect cells from oxidative stress.57 They also expose mHtt-expressing cells to a calcium overload. In addition, PPAR-c agonists enhance the population of mitochondria and the oxidative capacity of phosphorylation in human and animal cells.65,66
Multiple Sclerosis
Tissue damage in oligodendrocytes due to mitochondrial dysfunction has been linked to myelin destruction and impaired repair processes in multiple sclerosis (MS). There are focal areas of Waldenström’s macroglobulinemia damage in the CNS in MS where myelin is stripped off the axons and further axonal damage ensues.67,68 Many clinical reports on people have documented that MS patients exhibit signs of mitochondrial dysfunction. In one study, analyses of ten postmortem MS patient brains using qPCR revealed differential regulation of nuclear mitochondrial DNA (mtDNA) transcripts, with 26 transcripts downregulated. Additionally, mtDNA transcripts showed significant alterations, with 488 downregulated and 67 upregulated compared to controls, highlighting distinct transcriptional changes in the MS cortex. In the same samples, both complex I and complex III activities in motor cortex neurons were found to be reduced. Furthermore, a decrease in synaptic GABAergic components was also identified, indicating impaired neuronal function in the context of MS.69,70 In progressive MS patients, a positive correlation between ROS generation and mitochondria count in axons and astrocytes has also been reported (Figure 4).
The strain-induced increases in ROS are also related to the translation of mitochondrial proteins, including mtHSP70 and proteins from the ETC complex IV that are qualitatively and quantitatively increased compared with the brains of controls. MS is polymorphic, and genetic factors are reportedly responsible for the 25% variability of the disease. In addition, postmortem examination of brain tissue from MS patients, including lesioned areas, normal-appearing white matter (NAWM), and nonlesional cortex, has revealed evidence connecting mitochondrial failure to neurodegeneration. Electron microscopy of demyelinated spinal cord injuries reveals a marked reduction in the quantity of microtubules and mitochondria. Additional investigation reveals the reduced expression of mitochondrial genes unique to neurons in nonlesional tissue, oxidative damage to mtDNA, and decreased activity of mitochondrial enzyme complexes in lesioned tissue.69,71 Recent research on p66 indicates that pharmacologic inhibition of this ROS sensor and amplifier may offer neuroprotective effects in the setting of MS and possibly other neurodegenerative disorders as well, making it one of the novel therapeutic targets for mitochondrial preservation. New findings suggesting ATP synthase dimers form the PTP imply that this enzyme complex may also serve as a molecular switch to indicate the activation of pathways leading to cell death.72,73
Furthermore, axonal degeneration studies employing comparable techniques in the spinal cords of patients with secondary progressive MS revealed a 61% decrease in axonal density in chronic inactive lesions.74 Similarly, reduced nerve fiber densities were observed in the spinal cords of patients whose NAWM was analyzed.75 These postmortem findings have been validated by in vivo investigations employing magnetic resonance spectrometry, which analyzes specific resonance spectra peaks to ascertain the chemical makeup of brain matter. N-acetyaspartate (NAA), in particular, is thought to be a key indicator of neuronal integrity and is produced by neuronal mitochondria. In MS patients, reductions in NAA have been linked to relapses and neurological impairment.76–79
Friedreich’s Ataxia
Friedreich’s ataxia (FRDA) is an inherited autosomal recessive genetic disorder caused by a point mutation. This condition leads to the loss of sensation, impaired coordination, dysarthria, and progressive ataxia, typically manifesting in infancy or adolescence.80 However, it can lead to diabetic neuropathy, scoliosis, optic neuropathy, sensory neural hearing loss, and cardiomyopathy for some people. FRDA is caused by a biallelic loss-of-function mutation in the FXN gene which codes for the small mitochondrial protein frataxin.81 The genetic deficiency of FA is due to a mutation of the frataxin gene, a gene that has a GAA triplet repeat on the first intron that expands when atypical protein levels arise at the mutated site. Frataxin is a small protein localized to the mitochondria that plays a role in the assembly of iron–sulfur (Fe/S) clusters that are subunits of the respiratory chain complexes.82
Selective knockout of frataxin, a member of the FCP group, which has the mitochondrial signal sequence, has an impact on a wide range of mitochondrial functions. Biologically, its role seems to be involved in the assembly of Fe–S clusters, mitochondria, and the transfer of these clusters to enzymes containing this prosthetic group. Although ROS generation was applied initially in the first characterization of the mitochondrial dysfunction in FRDA, other specific secondary sources such as iron overload and ferroptosis, deficiency of antioxidant signaling pathway including Nrf2, and impaired mitochondrial biogenesis might be involved in some of the major pathophysiological processes in FRDA. Furthermore, reduced ATP content, neuronal loss, and worst oxidative injury in different compartments of the brain are made possible by the aggregation of iron deposits in the mitochondrion.83 Similarly, granule and glial cells differentiated from the murine cerebellum with a GAA repeat sequence mutation in the frataxin gene exhibit several detrimental effects, including depleted mitochondrial membrane potential (Δψm), increased ROS production, and impaired functions of complexes I, II, III, and IV. Additionally, these cells show heightened lipid peroxidation and increased neuronal death.84
Leigh Syndrome
Leigh syndrome (LS), the most common inherited mitochondrial disorder in infants, is pathologically characterized by astrogliosis and neurodegeneration, primarily affecting the brainstem and basal ganglia.85 LS is known to have a highly complex genetic background, with numerous causal mutations identified in genes and proteins involved in energy metabolism in both nuclear and mtDNA. Currently, mtDNA mutations account for approximately 10–20% of LS cases. Additionally, LS has been associated with genetic disorders involving complex I of the respiratory chain, further underscoring its intricate pathophysiology. Early in childhood, it manifests as psychomotor regression, dystonia, altered muscular tone, weakness, brainstem and cerebellar dysfunction (ataxia), vision loss, regression of previously reached milestones or missing ones, tachypnea, and seizures. After symptoms appear, death usually happens a few years later, mainly as a result of gradual respiratory failure.86,87 A laboratory investigation revealed metabolic acidosis with increased amounts of pyruvate, lactate, and CSF lactate. LS presents a formidable challenge due to its complex genetic underpinnings and the severe neurological impairments it causes. The interplay between various genetic mutations and energy metabolism dysfunction leads to a range of debilitating symptoms, ultimately culminating in life-threatening complications. Ongoing research into the molecular mechanisms underlying LS may pave the way for potential therapeutic strategies aimed at mitigating the impact of this devastating disorder, offering hope to affected individuals and their families.88–93
Conclusion
PD, AD, and HD represent significant challenges in neurodegenerative disorders, each with distinct genetic and biochemical underpinnings. PD is primarily associated with α-synuclein aggregation and mitochondrial dysfunction, leading to motor deficits and non-motor symptoms. In contrast, AD is characterized by the accumulation of amyloid plaques and tau tangles, resulting in cognitive decline and memory loss. HD, caused by CAG repeat expansions in the HTT gene, leads to progressive motor dysfunction and cognitive decline. FRDA is caused by mutations in the FXN gene, leading to frataxin deficiency, mitochondrial dysfunction, and a spectrum of neurological and systemic complications. LS, the most common inherited mitochondrial disorder in infants, involves a variety of genetic mutations that disrupt energy metabolism, leading to severe neurological impairment and early mortality.
Future Prospects
Future prospects for tackling neurodegenerative disorders hinge on advancing our understanding of their underlying molecular mechanisms. Promising avenues include the development of targeted therapies that address specific pathological features, such as α-synuclein aggregation in PD or amyloid plaque formation in AD. Additionally, research into the role of genetic and environmental factors may lead to more personalized approaches to treatment, allowing for early interventions tailored to an individual’s unique genetic profile. The exploration of neuroprotective strategies, such as the use of antioxidants and compounds that enhance mitochondrial function, may also offer new hope for slowing disease progression and improving patient outcomes.
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Cite this article as:
Safi SZ. Mitochondrial Dysfunction and Its Impact on Cellular Metabolism in Degenerative Diseases. Premier Journal of Neuroscience 2024;1:100002
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