Disruptions in mitochondrial function have been implicated in various neurodegenerative diseases. However, the specific role of mitochondrial proteins in the pathogenesis of dementia with Lewy bodies (DLB) remains poorly understood.
Objective
This study aims to investigate potential causal relationships between mitochondrial proteins and DLB risk using Mendelian randomization (MR) analysis.
Methods
Causal associations between 66 mitochondrial proteins (MPs) and DLB were assessed by MR analysis, utilizing data from comprehensive genome-wide association studies (GWAS), with various analytical methods, including the inverse variance weighted, MR-Egger, and weighted median. Cochran's Q statistics assessed the heterogeneity of instrumental variables.
Results
Genetic predispositions to increased levels of ES1 protein homolog and apoptosis-inducing factor 1 (AIF-1) were associated with an elevated risk of DLB. Conversely, genetic predispositions to increased levels of glutaredoxin-2 (GLRX-2), complement component 1 Q subcomponent-binding protein (C1QBP), and mitochondrial glutamate carrier 2 (GC2) were found to be protective against DLB. Sensitivity analyses revealed no heterogeneity or horizontal pleiotropy among the selected instrumental variables.
Conclusions
Our MR study identifies specific MPs potentially causally linked to DLB risk. These findings offer new insights into the MP-related mechanisms underlying DLB pathogenesis and highlight potential therapeutic targets.
ChenWZhaoHLiY. Mitochondrial dynamics in health and disease: mechanisms and potential targets. Signal Transduct Target Ther2023; 8: 333.
2.
NoratPSoldozySSokolowskiJD, et al.Mitochondrial dysfunction in neurological disorders: exploring mitochondrial transplantation. NPJ Regen Med2020; 5: 22.
3.
ReddyPHOliverDM. Amyloid beta and phosphorylated tau-induced defective autophagy and mitophagy in Alzheimer's disease. Cells2019; 8: 488.
4.
Bustamante-BarrientosFALuque-CamposNArayaMJ, et al.Mitochondrial dysfunction in neurodegenerative disorders: potential therapeutic application of mitochondrial transfer to central nervous system-residing cells. J Transl Med2023; 21: 613.
5.
MacdonaldRBarnesKHastingsC, et al.Mitochondrial abnormalities in Parkinson's disease and Alzheimer's disease: can mitochondria be targeted therapeutically?Biochem Soc Trans2018; 46: 891–909.
6.
ChenTTanJWanZ, et al.Effects of commonly used pesticides in China on the mitochondria and ubiquitin-proteasome system in Parkinson's disease. Int J Mol Sci2017; 18: 2507.
7.
MartinezTNGreenamyreJT. Toxin models of mitochondrial dysfunction in Parkinson's disease. Antioxid Redox Signal2012; 16: 920–934.
8.
WenJHHeXHFengZS, et al.Cellular protein aggregates: formation, biological effects, and ways of elimination. Int J Mol Sci2023; 24: 8593.
9.
PrinceMBryceRAlbaneseE, et al.The global prevalence of dementia: a systematic review and metaanalysis. Alzheimers Dement2013; 9: 63–75. e62.
10.
ShahmoradianSHLewisAJGenoudC, et al.Lewy pathology in Parkinson's disease consists of crowded organelles and lipid membranes. Nat Neurosci2019; 22: 1099–1109.
11.
UryuKRichter-LandsbergCWelchW, et al.Convergence of heat shock protein 90 with ubiquitin in filamentous alpha-synuclein inclusions of alpha-synucleinopathies. Am J Pathol2006; 168: 947–961.
12.
DicksonDWRuanDCrystalH, et al.Hippocampal degeneration differentiates diffuse Lewy body disease (DLBD) from Alzheimer's disease: light and electron microscopic immunocytochemistry of CA2-3 neurites specific to DLBD. Neurology1991; 41: 1402–1409.
13.
FornoLSNorvilleRL. Ultrastructure of Lewy bodies in the stellate ganglion. Acta Neuropathol1976; 34: 183–197.
14.
ChenCTurnbullDMReeveAK. Mitochondrial dysfunction in Parkinson's disease-cause or consequence?Biology (Basel)2019; 8: 20190511.
15.
HattonCReeveALaxNZ, et al.Complex I reductions in the nucleus basalis of Meynert in Lewy body dementia: the role of Lewy bodies. Acta Neuropathol Commun2020; 8: 103.
ScarlataSGolebiewskaU. Linking alpha-synuclein properties with oxidation: a hypothesis on a mechanism underling cellular aggregation. J Bioenerg Biomembr2014; 46: 93–98.
18.
BowdenJHolmesMV. Meta-analysis and Mendelian randomization: a review. Res Synth Methods2019; 10: 486–496.
SunBBMaranvilleJCPetersJE, et al.Genomic atlas of the human plasma proteome. Nature2018; 558: 73–79.
21.
ChiaRSabirMSBandres-CigaS, et al.Genome sequencing analysis identifies new loci associated with Lewy body dementia and provides insights into its genetic architecture. Nat Genet2021; 53: 294–303.
22.
ZhangTAnYShenZ, et al.Serum urate levels and neurodegenerative outcomes: a prospective cohort study and Mendelian randomization analysis of the UK biobank. Alzheimers Res Ther2024; 16: 106.
23.
EvansDMDavey SmithG. Mendelian randomization: new applications in the coming age of hypothesis-free causality. Annu Rev Genomics Hum Genet2015; 16: 327–350.
24.
StormCSKiaDAAlmramhiMM, et al.Finding genetically-supported drug targets for Parkinson's disease using Mendelian randomization of the druggable genome. Nat Commun2021; 12: 7342.
25.
SlobEAWBurgessS. A comparison of robust Mendelian randomization methods using summary data. Genet Epidemiol2020; 44: 313–329.
26.
BowdenJDavey SmithGBurgessS. Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression. Int J Epidemiol2015; 44: 512–525.
27.
BowdenJDavey SmithGHaycockPC, et al.Consistent estimation in Mendelian randomization with some invalid instruments using a weighted median estimator. Genet Epidemiol2016; 40: 304–314.
28.
StoreyJDTibshiraniR. Statistical significance for genomewide studies. Proc Natl Acad Sci U S A2003; 100: 9440–9445.
29.
GrecoMFMinelliCSheehanNA, et al.Detecting pleiotropy in Mendelian randomisation studies with summary data and a continuous outcome. Stat Med2015; 34: 2926–2940.
30.
BurgessSThompsonSG. Interpreting findings from Mendelian randomization using the MR-Egger method. Eur J Epidemiol2017; 32: 377–389.
31.
BurgessSBowdenJFallT, et al.Sensitivity analyses for robust causal inference from Mendelian randomization analyses with multiple genetic variants. Epidemiology2017; 28: 30–42.
32.
UtsumiSSakamotoKYamashitaT, et al.Presence of ES1 homolog in the mitochondrial intermembrane space of porcine retinal cells. Biochem Biophys Res Commun2020; 524: 542–548.
33.
ItoGTataraYItohK, et al.Novel dicarbonyl metabolic pathway via mitochondrial ES1 possessing glyoxalase III activity. BBA Adv2023; 3: 100092.
34.
ShinJHWeitzdoerferRFountoulakisM, et al.Expression of cystathionine beta-synthase, pyridoxal kinase, and ES1 protein homolog (mitochondrial precursor) in fetal Down syndrome brain. Neurochem Int2004; 45: 73–79.
DaugasESusinSAZamzamiN, et al.Mitochondrio-nuclear translocation of AIF in apoptosis and necrosis. FASEB J2000; 14: 729–739.
37.
OteraHOhsakayaSNagauraZ, et al.Export of mitochondrial AIF in response to proapoptotic stimuli depends on processing at the intermembrane space. EMBO J2005; 24: 1375–1386.
38.
ZhangXChenJGrahamSH, et al.Intranuclear localization of apoptosis-inducing factor (AIF) and large scale DNA fragmentation after traumatic brain injury in rats and in neuronal cultures exposed to peroxynitrite. J Neurochem2002; 82: 181–191.
39.
CaoGClarkRSPeiW, et al.Translocation of apoptosis-inducing factor in vulnerable neurons after transient cerebral ischemia and in neuronal cultures after oxygen-glucose deprivation. J Cereb Blood Flow Metab2003; 23: 1137–1150.
40.
BurguillosMAHajjiNEnglundE, et al.Apoptosis-inducing factor mediates dopaminergic cell death in response to LPS-induced inflammatory stimulus: evidence in Parkinson's disease patients. Neurobiol Dis2011; 41: 177–188.
41.
ChuCTZhuJHCaoG, et al.Apoptosis inducing factor mediates caspase-independent 1-methyl-4-phenylpyridinium toxicity in dopaminergic cells. J Neurochem2005; 94: 1685–1695.
42.
YalçınkayaNHayturalHBilgiçB, et al.Expression changes of genes associated with apoptosis and survival processes in Parkinson's disease. Neurosci Lett2016; 615: 72–77.
43.
PenederTMBauerJPiflC. Apoptosis-inducing factor in nigral dopamine neurons: higher levels in primates than in mice. Mov Disord2016; 31: 1729–1733.
44.
OgataFTBrancoVValeFF, et al.Glutaredoxin: discovery, redox defense and much more. Redox Biol2021; 43: 101975.
45.
GongXHuangMChenL. NRF1 Mitigates motor dysfunction and dopamine neuron degeneration in mice with Parkinson's disease by promoting GLRX m(6) A methylation through upregulation of METTL3 transcription. CNS Neurosci Ther2024; 30: e14441.
46.
GongXHuangMChenL. Mechanism of miR-132-3p promoting neuroinflammation and dopaminergic neurodegeneration in Parkinson's disease. eNeuro2022; 9: ENEURO.0393–21.2021.
47.
JohnsonWMYaoCSiedlakSL, et al.Glutaredoxin deficiency exacerbates neurodegeneration in C. elegans models of Parkinson's disease. Hum Mol Genet2015; 24: 1322–1335.
48.
AhmadFNidadavoluPDurgadossL, et al.Critical cysteines in Akt1 regulate its activity and proteasomal degradation: implications for neurodegenerative diseases. Free Radic Biol Med2014; 74: 118–128.
49.
Rodriguez-RochaHGarcia GarciaAZavala-FloresL, et al.Glutaredoxin 1 protects dopaminergic cells by increased protein glutathionylation in experimental Parkinson's disease. Antioxid Redox Signal2012; 17: 1676–1693.
50.
VermaARayABapatD, et al.Glutaredoxin 1 downregulation in the substantia nigra leads to dopaminergic degeneration in mice. Mov Disord2020; 35: 1843–1853.
51.
SaitoTUchiumiTYagiM, et al.Cardiomyocyte-specific loss of mitochondrial p32/C1qbp causes cardiomyopathy and activates stress responses. Cardiovasc Res2017; 113: 1173–1185.
52.
FogalVRichardsonADKarmaliPP, et al.Mitochondrial p32 protein is a critical regulator of tumor metabolism via maintenance of oxidative phosphorylation. Mol Cell Biol2010; 30: 1303–1318.
53.
LiYWeiYHaoW, et al.Porcine reproductive and respiratory syndrome virus infection promotes C1QBP secretion to enhance inflammatory responses. Vet Microbiol2020; 241: 108563.
54.
RaschdorfASünderhaufASkibbeK, et al.Heterozygous P32/C1QBP/HABP1 polymorphism rs56014026 reduces mitochondrial oxidative phosphorylation and is expressed in low-grade colorectal carcinomas. Front Oncol2020; 10: 631592.
55.
LiYWanOWXieW, et al.P32 regulates mitochondrial morphology and dynamics through parkin. Neuroscience2011; 199: 346–358.
56.
YagiMUchiumiTSagataN, et al.Neural-specific deletion of mitochondrial p32/C1qbp leads to leukoencephalopathy due to undifferentiated oligodendrocyte and axon degeneration. Sci Rep2017; 7: 15131.
57.
MahmoudSGharagozlooMSimardC, et al.Astrocytes maintain glutamate homeostasis in the CNS by controlling the balance between glutamate uptake and release. Cells2019; 8: 184.
58.
BassiSTripathiTMonzianiA, et al.Epigenetics of Huntington's disease. Adv Exp Med Biol2017; 978: 277–299.
59.
SolinasSFortiLCesanaE, et al.Fast-reset of pacemaking and theta-frequency resonance patterns in cerebellar Golgi cells: simulations of their impact in vivo. Front Cell Neurosci2007; 1: 4.
60.
HillenAEJHeineVM. Glutamate carrier involvement in mitochondrial dysfunctioning in the brain white matter. Front Mol Biosci2020; 7: 151.
61.
AndersonMABurdaJERenY, et al.Astrocyte scar formation aids central nervous system axon regeneration. Nature2016; 532: 195–200.
62.
HansCPSharmaNSenS, et al.Transcriptomics analysis reveals new insights into the roles of Notch1 signaling on macrophage polarization. Sci Rep2019; 9: 7999.
63.
TaberEGardnerWAJrWoodHAJr. Stimulation of gonadotrophin secretion in the chick. Endocrinology1965; 77: 756–758.
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