Mitochondrial Dysfunction in Genetic and Non-Genetic Parkinson’s Disease
Abstract
:1. Introduction
2. Juvenile- and Early-Onset Genetic PD and Mitochondria Dysfunction
2.1. Parkin (PARK2)
2.2. PINK1 (PARK6)
2.3. DJ-1 (PARK7)
2.4. ATP13A2 (PARK9)
2.5. PLA2G6 (PARK14)
2.6. FBXO7 (PARK15)
2.7. Vacuolar Protein Sorting 13C (VPS13C) (PARK23)
3. Late-Onset Genetic PD and Mitochondrial Dysfunction
3.1. SNCA (PARK1/PARK4)
3.2. LRRK2 (PARK8)
3.3. Omi/HtrA2 (PARK 13)
3.4. Vacuolar Protein Sorting 35 (VPS35) (PARK17)
3.5. Coiled-Helix-Coiled-Helix Domain Containing 2 (CHCHD2) (PARK22)
4. Juvenile Genetic Atypical Parkinsonian Syndromes and Mitochondrial Dysfunction
4.1. ATXN3
4.2. CLN3
4.3. GLB1
4.4. POLG
4.5. Hereditary Spastic Paraplegia (HSP)
5. Environmental Toxins, PD, and Mitochondrial Dysfunction
6. Converging Mechanisms in Parkinson’s Disease: The Mitochondrial Link Between Genetic and Non-Genetic Cases
7. Mitochondria-Targeted Therapeutic Approaches in PD
8. Conclusions and Future Perspectives
Author Contributions
Funding
Conflicts of Interest
References
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Gene | Protein and Mutation Type | Shared MT Alterations | Gene-Specific MT Alterations | Age of Onset (Motor Symptoms) | Clinical Consequences |
---|---|---|---|---|---|
Parkin (PARK2) [27,28,29,30,31] | E3 ubiquitin ligase AR (more than 130 mutations) |
|
| <40 years | Slow progression, dystonia; infrequent olfactory dysfunction and cognitive impairment |
PINK1 (PARK6) [27,30,31,32,33,34,35,36] | MT serine-threonine kinase AR (111 point, frameshift, and truncating mutations) |
|
| Mid-30s | Slow progression, dystonia, non -motor symptoms, occasionally psychiatric disorders |
DJ-1 (PARK7) [37,38,39,40] | Peptidase C56 family AR (homozygous deletions or point mutations) |
|
| <50 years | Slow progression, early onset of motor symptoms, amyotrophy, cognitive impairment, acute behavioral disturbances |
ATP13A2 (PARK9) [41,42,43,44] | Neuronal lysosomal type 5 P-type ATPase AR (loss-of-function mutations) |
|
| <20 years | Dementia, pyramidal degeneration, spasticity, supranuclear gaze palsy |
PLA2G6 (PARK14) [3,45,46,47] | Ca2+-independent phospholipase A2β AR (more than 18 variants) |
|
| Adolescence-early 20s | Dystonia, gait impairment, speech difficulties, spasticity, myoclonus, neuropsychiatric and cognitive disorders |
FBXO7 (PARK15) [48,49,50,51,52] | F-box proteins (FBPs) adaptor protein member AR (3 point mutations, homozygous truncating FBXO7 mutation, compound heterozygous mutations) |
|
| Childhood | Tremor, rigidity, bradykinesia, pyramidal signs |
VPS13C (PARK23) [53,54] | Vacuolar sorting proteins 13 family AR (truncating mutations) |
|
| Early 20s | Lewy-body inclusions, cognitive decline, axial symptoms, dysautonomia |
Gene | Protein and Mutation Type | Shared MT Alterations | Gene-Specific MT Alterations | Age of Onset (Motor Symptoms) | Clinical Consequences |
---|---|---|---|---|---|
SNCA (PARK1/ PARK4) [15,94,95,96,97,98] | α-synuclein AD (p.A53T, p.A30P, p.E46K, p.G51D, p.A53E, duplications, triplications) |
|
| 20–85 years | Resting tremor, bradikinesia, rigidity, dysphagia, dysarthria, cognitive deficits |
LRRK2 (PARK8) [99,100,101,102,103,104,105,106,107,108,109] | Leucine-rich repeat kinase 2 AD (G2019S) |
|
| 30–80 years | Bradykinesia, rigidity resting tremor, gait abnormalities, postural instability, orthostatic hypotension, hallucinations, dementia, less frequent RBD and anosmia |
Omi/HtrA2 (PARK 13) [110,111,112] | Serine protease (p.G399S and other genetic variants) |
|
| 40–70 years | Bradykinesia, muscular rigidity, tremor |
VPS35 (PARK17) [113,114,115,116,117] | hVPS35 AD (p.D620N and other mutations) |
|
| Around 50 years | Resting tremor, rigidity, bradykinesia, postural reflexes alterations |
CHCHD2 (PARK22) [118,119,120,121] | CHCHD2 AD (missense mutations) |
|
| Mid-50s | Early essential tremor, restless legs syndrome, depression, mild cognitive deficits |
Gene | Protein and Mutation Type | Shared MT Alterations | Gene-Specific MT Alterations | Age of Onset (Motor Symptoms) | Clinical Consequences |
---|---|---|---|---|---|
ATXN3 [148,149,150,151] | Ataxin-3 protein AD (CAG repeat expansion) |
|
| Adolescence-middle age | Progressive cerebellar ataxia, pyramidal signs, dystonic-rigid extrapyramidal syndrome, peripheral amyotrophy, generalized areflexia, external ophthalmoplegia, action-induced facial and lingual fasciculations, bulging eyes |
CLN3 [152,153] | CLN3 protein AR |
|
| Childhood (4–7 years) | Early-onset progressive vision loss, personality changes, behavioral problems, slow learning, seizures, progressive motor function loss |
GLB1 [154] | β-galactosidase (β-gal) AR (cleavage of the terminal β-1,4-linked galactose residue from GM1 gangliosides) |
|
| Childhood-adolescence | Dystonia/hypotonia, speech difficulty, hepatosplenomegaly, developmental regression, seizures, visual impairment |
POLG [155,156,157,158] | DNA Polymerase subunit gamma |
|
| Early childhood to third–fourth decade | Various clinical features depending on the specific syndrome |
Toxic Agent | Toxin Type | First Identification | Mitochondrial Alterations |
---|---|---|---|
Rotenone [208,214,228,229,230] | Crystalline isoflavone, used as pesticide, insecticide, and piscicide | 1990s epidemiological studies in humans; first in vivo PD model in rats in 2000 |
|
MPTP [206,207,210,231] | Tetrahydropyridine, precursor of MPP+ | Late 1970s–early 1980s toxicity found in humans (after contaminated intravenous drug use); first animal model in 1984 (squirrel monkey) |
|
6-OHDA [226,232] | Dopamine-derived benzenetriol | Toxicity described in 1959; first PD (akinesia) model in 1968 |
|
Category | Agents | Mechanism of Action | Evidence Level |
---|---|---|---|
ETC and Antioxidants | CoQ10, Idebenone, Methylene Blue, Creatine | Bypass complex I, ETC facilitation, ROS neutralization | Preclinical and Limited Clinical |
Phytochemicals | Resveratrol, Curcumin, Quercetin | Antioxidant activity, mitophagy, mitochondrial fusion | Preclinical |
Bile Acids | UDCA, Taurine-UDCA | Enhances ATP, reduces ROS, stabilizes membrane potential | Preclinical |
Metal Homeostasis | Deferiprone, Deferoxamine | Chelation of Fe, Cu; reduces oxidative stress | Preclinical |
Peptides/Proteins | GLP-1 Agonists, SIRT1/SIRT3 | Mitochondrial biogenesis, metabolic regulation | Preclinical and Mixed Clinical |
Signaling Modulators | MitoQ, Ferulic Acid, RNS60, TPNA10168 | Biogenesis via AMPK/PGC-1α, antioxidant response via Nrf2/ARE | Preclinical |
Mitochondrial Dynamics | Mdivi-1, Compound A | Inhibits fission and apoptosis pathways | Preclinical |
Mitophagy | IU1 | Induces selective clearance of dysfunctional mitochondria | Preclinical |
Experimental Approaches | P13 Inhibition, BDV X Protein | Apoptosis regulation, mitochondrial integrity restoration | Experimental |
Mitochondrial Transplantation | Allogeneic Mitochondria | Mitochondrial replacement therapy | Preclinical |
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© 2025 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Lucchesi, M.; Biso, L.; Bonaso, M.; Longoni, B.; Buchignani, B.; Battini, R.; Santorelli, F.M.; Doccini, S.; Scarselli, M. Mitochondrial Dysfunction in Genetic and Non-Genetic Parkinson’s Disease. Int. J. Mol. Sci. 2025, 26, 4451. https://doi.org/10.3390/ijms26094451
Lucchesi M, Biso L, Bonaso M, Longoni B, Buchignani B, Battini R, Santorelli FM, Doccini S, Scarselli M. Mitochondrial Dysfunction in Genetic and Non-Genetic Parkinson’s Disease. International Journal of Molecular Sciences. 2025; 26(9):4451. https://doi.org/10.3390/ijms26094451
Chicago/Turabian StyleLucchesi, Martina, Letizia Biso, Marco Bonaso, Biancamaria Longoni, Bianca Buchignani, Roberta Battini, Filippo Maria Santorelli, Stefano Doccini, and Marco Scarselli. 2025. "Mitochondrial Dysfunction in Genetic and Non-Genetic Parkinson’s Disease" International Journal of Molecular Sciences 26, no. 9: 4451. https://doi.org/10.3390/ijms26094451
APA StyleLucchesi, M., Biso, L., Bonaso, M., Longoni, B., Buchignani, B., Battini, R., Santorelli, F. M., Doccini, S., & Scarselli, M. (2025). Mitochondrial Dysfunction in Genetic and Non-Genetic Parkinson’s Disease. International Journal of Molecular Sciences, 26(9), 4451. https://doi.org/10.3390/ijms26094451