Neurodegenerative Disorders Associated With Genes Of Mitochondria
Jun 28, 2024
Abstract
Background: Over the last decade, aggregating evidence suggested that there is a causative link between mutation in genes associated with mitochondrial dysfunction and the development of several neurodegenerative disorders.
The relationship between mitochondria and memory has received much attention. Mitochondria are energy factories within cells that are responsible for synthesizing the energy needed by cells. Every cell in the human body contains mitochondria, including nerve cells and brain cells. The relationship between mitochondria and brain memory has been widely studied, and studies have shown that there is a close and important relationship between the two.
Studies have shown that changes in mitochondrial function can affect the energy supply of brain cells and neuronal cells. Therefore, when mitochondrial function decreases, the ability of the brain and nerve cells to process information will also decrease. This will lead to memory loss and other neurological disorders.
However, given the importance of mitochondria to the human body, many researchers have begun to develop methods to improve mitochondrial function. These methods are based on lifestyle improvements such as a healthy diet and exercise, which have been shown to play an important role in preventing or reversing mitochondrial function damage at an early stage.
In addition, some cytokines and antioxidants can also enhance mitochondrial function. For example, cytokines such as vitamin C, vitamin E, carotenoids, etc. can play a certain protective role on mitochondria and increase the level of antioxidants in mitochondria. These help prevent mitochondrial damage, enhance the energy needs of brain cells, and improve people's memory.
In summary, there is indeed a close relationship between mitochondria and human memory. Therefore, we should actively take measures to improve mitochondrial function and maintain a good lifestyle to improve our brain cell energy supply and memory. It can be seen that we need to improve memory, and Cistanche can significantly improve memory because it can also regulate the balance of neurotransmitters, such as increasing the levels of acetylcholine and growth factors, which are very important for memory and learning. In addition, Cistanche can also improve blood flow and promote oxygen delivery, which can ensure that the brain obtains sufficient nutrition and energy, thereby improving brain vitality and endurance.
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Main text: Recent structural and functional studies associated with mitochondrial genes have shown that mitochondrial abnormalities possibly lead to mitochondrial dysfunction. Several studies on animal models of neurodegenerative diseases and mitochondrial genes have provided compelling evidence that mitochondria are involved in the initiation as well as the progression of diseases such as Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD), and Friedreich ataxia (FA).
Conclusion: In this mini-review, we have discussed the different etiologic and pathogenesis connected with mitochondrial dysfunction and relevant neurodegenerative diseases that underlie the dominant part of mitochondrial genes in disease development and its progress.
Keywords: Mitochondrial genes, Parkinson's disease, Alzheimer's disease, Huntington's disease, Mutation, Friedreich ataxia.
Background
Mitochondria allied with the formation of adenosine triphosphate (ATP) through the oxidative phosphorylation process. However, mitochondria also take part in a lot of necessary cellular functions like iron and calcium homeostasis, steroids, pyrimidines, and heme biosynthesis [1, 2]. Mitochondria have both inner and outer membranes, which are impermeable to charged ions including all other molecules.
The ATP generation process occurs at the inner membrane of mitochondria through electron donation by nicotinamide adenine dinucleotide (NAD) or flavin adenine dinucleotide (FAD) equivalents formed by the tricarboxylic acid (TCA) cycle. This process is called as the electron transport system [3, 4]. Mitochondrial DNA (mtDNA) involves the circular structure of 569, 16 base pairs which are active in the synthesis of proteins and mitochondrial ribonucleic acids (RNSs). This mtDNA encodes 13 polypeptides, 22 ribosomal RNAs, and 22 transfer RNAs, all of which are important for ATP formation and electron transport, consequently for normal cellular physiology.
There are many human diseases that are strongly related to mutated mitochondrial genes [5–8]. Oxidative damage and subsequent dysfunction are occurring to mitochondria which is known to be a major site of free radical generation in cells [9]. The mitochondrial genome (mtDNA) is more susceptible to oxidative damage as compared to the nuclear DNA [10]. Due to the decline of defense mechanisms in the cell, oxidative stress occurs and damages the nucleic acids. If the damaged DNA is not repaired then it is considered to be highly mutagenic upon DNA replication [11].
Basic mitochondrial genetics
It is well known that mitochondria contribute to aging and neurodegeneration through the accumulation of mtDNA mutation and generation of reactive oxygen species (ROS) [12]. Excessive production of ROS stimulates several signaling molecules that governs the endogenous mitochondrial apoptotic pathway. Similarly, mtDNA dysfunction can be induced by many signaling molecules that are regulated by nuclear genes and intrinsic factors involved in mitochondrial metabolism. Thus, it is speculated that mtDNA is directly linked with the nuclear signaling pathway and thus, can influence aging process and associated neurodegeneration [13, 14]. Given this background, this review summarizes some possible pathophysiology of mitochondrial dysfunction associated with a mutation in genes, as a cause of Parkinson's disease (PD), Alzheimer's disease (AD), Friedreich's ataxia (FRDA), and Huntington's disease (HD).
Main text
Mitochondrial genes in major neurodegenerative disorders
Parkinson's disease (PD)
Parkinson's disease is one of the progressive and most common neurodegenerative diseases characterized by some common clinical features such as bradykinesia, rigidity, tremor, and some non-motor symptoms such as depression, apathy, and sleep disorders [15]. Recently, several reports demonstrated the involvement of mitochondrial genes in the pathogenesis of PD.
Synuclein alpha (SNCA)
SNCA encodes for α-Synuclein (α-Syn), a small polypeptide consisting of 140 amino acids. Even though its role is not discovered, it has been observed that it mediates the release of neurotransmitters at the presynaptic terminals and interacts with membranes of organelles, including mitochondria. Interestingly, α-Syn has shown an influence on the structure of mitochondria and its function [16]. Initially, α-Syn was associated with PD as an important component of Lewy bodies [17].
Elevated levels of wildtype (WT) α-Syn to a larger extent, lead to PD-associated mutations such as E46K, H50Q, and A53T which induces in vivo and in vitro mitochondrial fragmentation and reactive oxygen species (ROS) formation. Further, α-Syn is confined to mitochondria-associated membranes (MAM), a special structure that forms an interface between the mitochondria-endoplasmic reticulum (ER) and is important for the regulation of apoptosis and Ca2+ signaling. Mutant α-Syn was found to decrease binding to MAM and elevation in mitochondrial fragmentation, suggesting a role for α-Syn in mitochondrial morphology regulation [18, 19]. Mutant α-Syn was reported as the reason for the separation of mitochondria and ER at MAM, which impairs Ca2+ exchange and reduces ATP formation in mitochondria [20].
Additionally, a recent study has reported that α-Syn also affects mitochondrial biogenesis through peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC1α) [21]. Accordingly, treatment of dopaminergic neurons containing A53T with mitochondrial toxins such as S-nitrosylation of transcription factor myocyte-specific enhancer factor 2C (MEF2C), leads to reduced mitochondrial biogenesis through downregulation of PGC1α [22]. α-synuclein aggregation is a pathological characteristic common to PD, as well as other neurodegenerative diseases, such as dementia with Lewy bodies (DLB), and multiple system atrophy (MSA) which are collectively called "α-synucleinopathies" [22].
Leucine-rich repeat kinase 2 (LRRK2)
In humans, the LRRK2 gene encodes leucine-rich repeat kinase 2 (LRRK2) which is also called mandarin and PARK8 is a kinase enzyme [23, 24]. Mutation in LRRK2 causes penetrant autosomal dominant type of PD and it is the most common cause of familial PD. LRRK2 is a type of protein kinase that is multifunctional and LRRK2 mutants exert their pathogenic action by elevating kinase activity. The mutant LRRK2 may contribute to elevating the mitochondrial toxins, ROS production, and defects in mitochondrial dynamics as shown in Fig. 1 [22, 25]. In addition to this, a common heterozygous mutation, 2877510G→A leads to idiopathic PD. This heterozygous mutation leads to the formation of glycine to serine amino acid substitution at codon 2019 (Gly2019Ser) [22].
Vacuolar protein sorting-associated protein 35 (VPS35)
The relation between VPS35 and PD was observed first in European PD cohorts with a history of an autosomal dominant inheritance [26–28]. The key role of VPS35 in mitochondria is the mitochondrial dynamics regulation through interaction with mitochondrial fusion/fission proteins. Multiple studies have reported that mutation in VPS35 can trigger mitochondrial fragmentation, which leads to neurodegeneration [29, 30]. Apart from this, it was reported that increased interaction of dynamin-like protein (DLP) 1 with VPS35 mutant, supports change of the mitochondrial DLP1 complexes through the mitochondria-derived vesicle–dependent trafficking of various complexes to lysosomes for degradation. Interestingly, oxidative stress elevates the VPS35- DLP1 interaction, which is also observed to be raised in sporadic PD patients [30].
Coiled-coil-helix-coiled-coil-helix domain 2 (CHCHD2)
Recently, it has been reported that CHCHD2 mutation causes late-onset, autosomal dominant PD in three Japanese families [31]. Mitochondrial inter-membrane space protein CHCHD2 shows functions in the nucleus and mitochondria. In normal conditions, CHCHD2 is bound to mitochondrial complex IV and mutation of CHCHD2 has shown decreased mitochondrial complex IV activity, which results in mitochondrial fragmentation and increases in ROS production [32, 33]. Interestingly, CHCHD2 was found that translocate in the nucleus and act as a transcription factor under stress conditions. Furthermore, several models expressing mutants associated with PD also showed biochemical and structural mitochondrial abnormalities leading to motor dysfunction and dopaminergic neurodegeneration. The mutant CHCHD2 leads to impairment of mitochondrial function which results in the progression of PD [34].
Parkin protein gene (PARK2)
Parkin protein in humans is encoded by the PARK2 gene. Mutations in the PARK2 gene cause Parkinson's disease, especially autosomal recessive juvenile Parkinson's disease. Parkin is a cytosolic E3 ubiquitin ligase. Target proteins for proteasomal degradation are ubiquitinated by Parkin [35, 36]. Parkin plays a key role in maintaining healthy mitochondria by regulating their biogenesis and degradation through mitophagy [36]. The removal of damaged mitochondria from the healthy mitochondrial pool allows their degradation through the autophagy lysosomal pathway by the process of mitophagy. Parkin is also known to regulate the functional mitochondrial pol by mitochondrial biogenesis regulation [37]. In normal conditions, it interposes the degradation of the parkin interaction substrate (PARIS), leading to transcriptional activation of nuclear translocation of PGC1α and mitochondria-associated genes [38]. Accordingly, loss in Parkin function facilitates PARIS to accumulate and suppress mitochondrial biogenesis, which results in mitochondrial functional defects.
PTEN-induced kinase 1 (PINK1)
Mutations in PINK1 are very known common causes of the autosomal recessive early-onset PD. PINK1, which plays an important role in balancing mitochondrial homeostasis, impairs several aspects of mitochondrial biology, including morphology, degradation, and trafficking [39–41]. The most widely reported role of PINK1 is in mitochondria mitophagy, promoting the removal of damaged mitochondria by activating and recruiting Parkin [42]. PINK1 activates Parkin by two mechanisms: (1) trans-activation by phosphorylation of ubiquitin at S65 and further binding to Parkin and (2) direct Parkin phosphorylation at S65. Loss of PINK1 leads to a wide range of mitochondrial dysfunction in mice, cell models, and Drosophila [41]. These mainly result in the loss of PINK1 mitophagy. Mutant PINK1 protein leads to the development of improperly folded proteins in the mitochondria. Mutations in the threonine/serine kinase domain of PINK1 have been found in Parkinson's patients [39, 43]. There are several studies reported that PINK1 is a mitochondrial site and this may show a protective effect on cells that are affected by the mutations, which leads to increased susceptibility to cellular stress. This suggests a direct relation between the pathogenesis of PD and mitochondria [39].
ATPase cation transporting 13A2 (ATP13A2)
An enzyme found in humans, probable cation transporting ATPase 13A2, is mainly involved in the transport of divalent transition metal cations [44]. Mutant ATP13A2 causes Kufor-Rakeb syndrome (KRS). It is an autosomal recessive juvenile-onset PD [45]. ATP13A2 mitochondrial function was first recognized in mitochondrial dysfunction in KRS patient-derived skin fibroblast [46]. Several studies have also reported that ATP13A2-deficient models demonstrate mitochondrial dysfunction, decreased ATP production, elevated ROS production, and increased mitochondrial fragmentation as shown in Fig. 1. Additionally, deregulation of Zn2+ metabolism leads to lysosomal dysfunction, which further leads to defective mitophagy. This shows that associated pathways are involved in the pathogenesis of PD [47, 48].
Alzheimer's disease (AD)
Alzheimer's disease (AD) is a very common and disabling neurodegenerative disorder which is a form of dementia of the aged [49]. Its incidence increases along with age and thereby it is a significant public health concern. In the late stages of AD, severe memory loss is observed and serious neurodegeneration is obvious [50].
Amyloid protein precursor (APP)
Highly conserved and an ancient protein APP is a precursor, that produces amyloid beta (Aβ), a polypeptide that contains 37 to 49 amino acid residues. In the brain of Alzheimer's patients, the amyloid fibrillar form of Aβ which is amyloid plaques was observed [51]. Mutations in the APP gene cause familial susceptibility to Alzheimer's disease. It has been reported that APP duplications or APP mutations located around the β cleavage site lead to the overall increase in production of Aβ species which causes early-onset Alzheimer's disease (EOAD) [51].
Presenilin
Presenilin, a sub-component of γ-secretase, is responsible for the APP cutting. A γ-secretase can intercept APP at multiple points within protein, which leads to the formation of Aβ of different lengths about Alzheimer's disease; 40 and 42 amino acids long [52, 53]. It has been reported that Aβ 42 has more chances to form plaques in the brain than Aβ 40. Mutant presenilin leads to an elevation in the ratio of Aβ 42 production as compared to Aβ 40. This mutation also results in a decrease in amyloid precursor protein-derived amyloid β-peptide generation [54]. The loss in presenilin function causes an incomplete degradation of the amyloid β-peptide which contributes to an increased vulnerability of the brain and therefore becomes a cause of EOAD [55].
AvaII16390
The human mitochondrial genome contains AvaII in a non-coding region. The frequency of AvaII16390 in the Alzheimer's brain was investigated [50]. The DNA sequence analysis of the AvaII16390 has shown that the major change in the sequence was a C to T transition mutation at position 5 of the AvaII site [56]. Increased frequency of AvaII16390 in the Alzheimer's brain may contribute to the formation of oxidative radicals. Some studies found no notable relation between the person's age and AvaII16390 frequency [57].
Cytochrome c oxidase CO1 and CO2
Cytochrome c oxidase (CO) is encoded exclusively by two mitochondrial genes, CO1 (subunits I) and CO2 (subunits II). It was found that cytochrome c oxidase activity declined in peripheral tissue and the brain especially in late-onset AD patients [58]. A higher frequency of specific missense mutations in the mitochondrial CO1 and CO2 genes were AD showed a strong association between the genes and AD. A mutant mitochondrial DNA molecule revealed a decrease in CO activity and elevated production of ROS [59]. It has been reported that a CO defect may directly participate in a cascade of events that result in AD. They again identified that AD mothers' asymptomatic children had more number of these mutations than children of AD fathers. These mutations are maternally inherited [60].
16S rRNA
Mitochondrial 16S rRNA alteration in most of the AD patients is considering the possible reason for its involvement in AD but additional studies are required to clarify the possible role of rRNA mutations in pathogenesis. One of the possible roles of genetic mutation is to interfere with the normal tRNA protection activity [61].
Apolipoprotein E (APO E)
APO E consists of three different isoforms such as apo e2, e3, and e4 which are different at 299 amino acid chains [62]. The presence of the APO E e4 allele confers considerable risk for late-onset AD, which may be sporadic or familial [63]. The brain APO E is the principal cholesterol carrier involved in the disease of cholesterol dyshomeostasis [64]. Existing studies suggest that a rise in the cholesterol content increases the risk of developing AD [65].
Huntington's disease (HD)
Huntington's disease (HD) is an untreatable, late-onset, slowly progressive, neurodegenerative disease caud a by genetic mutatithatich leads to an expanded polyglutamine (polyQ) for which no suitable therapy is currently available [66, 67]. HD is identified by ataxia, chorea, and dementia [68]. Another type of peptide having 23 aa known as P42 shows protective action by preventing polyQ-hHtt aggregation [69]. The neuropathological classification of HD disease involves 5 classes (0–IV). Among all the classes, class IV is considered to be more severe which shows increased loss of neurons [70].
Huntington (Htt) gene
Htt is a 3144 amino acid-containing protein having a molecular weight of about 350 kDa, ever present in the brain as well as peripheral tissues [71]. Htt is mostly found in the cell organelles like cytoplasm, along with the mitochondria [72]. The role of Htt protein is not well established but various studies show that it may play a vital role in the development of neurons [66, 73]. Huntington protein is essential for regulating the axonal transport of vesicles including brain-derived neurotrophic factor (BDNF) [74].
Mitochondrial structural genes (Drp1, Fis1, Mfn1, Mfn2 and Opa1)
Different forces like fission and fusion are responsible for changing the morphology of mitochondria [75]. Various mitochondrial structural genes are also known as shaping proteins because they are responsible for maintaining the proper morphology of mitochondria [76]. Free radicals in mitochondria activate the Dynamin-related protein 1 (Drp1) and mitochondrial fission 1 (Fis1) protein which are responsible for mitochondrial fission.
Mitochondrial fusion proteins are Mfn1 (mitofusin 1), Mfn2 (mitofusin 2), and Opa1 (optic atrophy 1) which are the GTPase proteins [77]. Increased expression of fission proteins as well as decreased expression of fusion proteins may be the reason for the change in mitochondrial dynamics which leads to neuronal damage in HD brain [78].
Friedreich's ataxia (FA)
The neurodegenerative disorder Friedreich's ataxia (FRDA) is an adolescent autosomal recessive disorder caused by mutations in frataxin, a mitochondrial protein whose function remains controversial [79]. It has a prevalence of approximately 1 in 50,000. Dysarthria, progressive ataxia, skeletal deformities, pyramidal features, hypertrophic cardiomyopathy, and hyporeflexia are the major clinical signs of FA [80]. Some established reports show that mitochondrial enzymes such as pyruvate glutamate dehydrogenase, α-ketoglutarate dehydrogenase, and dehydrogenase activities are decreased in FA cells [81–83].
Frataxin
Friedreich's ataxia is caused by the mutation of a 210 amino acid protein called frataxin [84]. Although the exact role is not fully understood, it may be vital for the proper functioning of mitochondria. The main cause involves the tri-nucleotide GAA repeat expansion within the intron of the frataxin gene [85]. The increased iron content has been reported in mitochondria suggesting that frataxin plays a major role in transportation of the iron [86]. Mutated frataxin results in aconitase and mitochondrial Fe-S (iron-sulfur) respiratory enzyme deficiency in FA [87].
Conclusion
There are several reported factors wthatcause neurodegenerative disorders such as PD, AD, HD, and FRDA. Among all these, mitochondrial dysfunction plays an important role in the etiology and pathogenesis of these disorders. Hence, this article is mainly focusing on the causality relationship between gene-associated mitochondrial dysfunction which leads to the development of neurodegenerative disorders as shown in Table 1. TAdditionalstudies are needed to clarify the possible pathogenic role of mtDNA mutations. Rapid advances in these types of knowledge have created an unmatched and great opportunity tforthe study of mitochondrial dysfunction in neurodegenerative disorders. This also creates an opportunity for the research and development of drugs or therapies that target mitochondrial genes, whose mutation leads to the generation of neurodegenerative disorders.
Abbreviations
ATP: Adenosine triphosphate; NAD: Nicotinamide adenine dinucleotide; FAD: Flavin adenine dinucleotide; TCA: Tricarboxylic acid; RNAs: Ribonucleic acids; PD: Parkinson's disease; AD: Alzheimer's disease; HD: Huntington's disease; FRDA: Friedreich's ataxia; α-Syn: α-synuclein; WT: Wild type; ROS: Reactive oxygen species; MAM: Mitochondria-associated membranes; ER: Endoplasmic reticulum; MSA : Multiple system atrophy; DLB : Dementia with Lewy bodies; DLP: Dynamin-like protein; PGC1α: Proliferator-activated receptor gamma coactivator 1-α; MEF2C: Myocyte-specific enhancer factor 2C; LRRK2: Leucine rich repeat kinase 2; VPS35: Vacuolar protein sortingassociated protein 35; CHCHD2: Coil-helix-coiled-coil-helix domain 2; PARK2: Parkin 2; PARIS: Parkin interaction substrate; PINK1: PTEN-induced kinase 1; ATP13A2: ATPase 13A2; APP: Amyloid protein precursor; Aβ: Amyloid beta; CO: Cytochrome c oxidase; rRNA: Ribosomal ribonucleic acid; APOE: Apolipoprotein E; PolyO: Polyglutamine; Htt : Huntington; Drp1: Dynamin-related protein 1; Fis1: Fission 1; Mfn1: Mitofusin 1; Opa1: Optric atrophy 1; Tomm40 : Translocase of outer membrane 40; CypD: Cyclophilin D; GAA: Guanine-adenine-adenine.
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Authors' contributions
VM contributed to the preparation of primary content. He performed an extensive literature survey and compiled the content. NW contributed to the preparation of figures and tables. PT contributed to checking of manuscript and correcting grammatical mistakes. MU contributed to the preparation of the figure. AU contributed to the finalization of the manuscript and its correction. MK contributed to the finalization of content, preparation of the concrete manuscript, and the schematic presentation of content. BT contributed to checking of manuscript and correcting grammatical mistakes. All authors have read and approved the final manuscript.
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Author Details
National Institute of Pharmaceutical Education and Research, Hyderabad, Telangana 500037, India. 2 Springer Nature Technology and Publishing Solutions (SNTPS), Pune, India. 3 Smt. Kishoritai Bhoyar College of Pharmacy, Kamptee, Nagpur, Maharashtra 441002, India. 4 SNJB's Shriman Sureshdada Jain College of Pharmacy, Nemi Nagar, Chandwad, Nashik 423101, India. 5 Smt. Kishoritai Bhoyar College of Pharmacy, Kamptee, Nagpur, Maharashtra 441002, India.
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