Integrative Biomedical Research
Integrative Biomedical Research (Journal of Angiotherapy) | Online ISSN 3068-6326
463
Citations
2m
Views
801
Articles
Volume 10 Number 1 2026
REVIEWS (Open Access)
Genomic Cross-Talk, Broken Bridges Mitochondrial–Nuclear Signaling Failure as a Unifying Mechanism and Druggable Frontier in Parkinson's Disease
Osama Abdel-Hameed Majeed 1*, Makarim Qassim Al-Lami 1, Gheyath Al-Gawwam 2
Integrative Biomedical Research 10 (1) 1-14 https://doi.org/10.25163/biomedical.10110926
Submitted: 21 July 2026 Revised: 12 September 2026 Accepted: 22 September 2026 Published: 24 September 2026
Abstract
Parkinson's disease (PD) is, at its core, a failure of conversation — a breakdown in the ceaseless molecular dialogue that the nucleus and the mitochondrion must sustain if a dopaminergic neuron is to survive its own metabolic demands. This review asks, and tries to answer honestly, how that dialogue collapses. Dopaminergic neurons of the substantia nigra pars compacta rely on an uninterrupted, bidirectional exchange between the nuclear and mitochondrial genomes — anterograde signals that sustain organelle biogenesis, and retrograde signals that report back on mitochondrial stress. In PD, this exchange is progressively disrupted, converging on bioenergetic collapse, oxidative injury, and neuroinflammation. We synthesized peer-reviewed mechanistic and preclinical studies (2009–2026) addressing mitochondrial-nuclear crosstalk in PD, drawn from a defined, reproducible literature search of the sources cited throughout this manuscript, spanning molecular, cellular, and systemic (multi-organ) levels of analysis.Four interlocking hubs emerged consistently across the evaluated literature: (i) the PINK1/Parkin–PARIS–PGC-1α/Nrf2 biogenesis axis; (ii) the geranylgeranylation-dependent GBP2/NIX alternative mitophagy pathway; (iii) retrograde apoptotic and innate-immune execution through AIF, cGAS-STING, and PANoptosis; and (iv) systemic amplification via glial-neuronal and multi-organ (gut-, liver-, lung-, heart-, muscle-, and bone-brain) axes. Pharmacological correction of these nodes — with silybin, cannabidiol, gentiopicroside, and the geranylgeranylation inhibitor GGTI298 — consistently restored mitochondrial quality control and attenuated dopaminergic loss in preclinical models. Mitochondrial-nuclear crosstalk is not a peripheral detail of PD biology; it is arguably the organizing principle beneath much of what we call “PD pathology.” Multi-target strategies that simultaneously restore biogenesis, mitophagy, and antioxidant signaling represent a genuinely promising — if still early — route toward disease modification.
Keywords: Parkinson's disease; mitochondrial-nuclear crosstalk; PINK1/Parkin; PGC-1α; Nrf2 signaling; mitophagy; neuroinflammation
References
Bloem, B. R., Okun, M. S., & Klein, C. (2021). Parkinson's disease. The Lancet, 397(10291), 2284–2303. https://doi.org/10.1016/S0140-6736(21)00218-X
Buneeva, O., Fedchenko, V., Kopylov, A., & Medvedev, A. (2020). Mitochondrial dysfunction in Parkinson's disease: Focus on mitochondrial DNA. Biomedicines, 8(12), Article 591. https://doi.org/10.3390/biomedicines8120591
Cui, W., Wang, T., & Feng, J. (2026). Upregulated GBP2 exacerbates Parkinson's disease pathogenesis by impairing NIX-dependent mitophagy. Redox Biology, 90, Article 104029. https://doi.org/10.1016/j.redox.2026.104029
Gao, Y., Tang, X., Yao, J., Sun, T., Chen, Y., Cheng, C., Yang, J., Wang, B., Liu, A., Yang, L., & Zhenxiong, M. (2026). Targeting the bile acid receptor TGR5 with Gentiopicroside to activate Nrf2 antioxidant signaling and mitigate Parkinson's disease in an MPTP mouse model. Journal of Advanced Research, 80, 977–990. https://doi.org/10.1016/j.jare.2025.05.039
García-Yagüe, A. J., Esteras, N., Dinkova-Kostova, A. T., Rojo, A. I., Shiels, P. G., Dinnyes, A., Tamas, V., van Goor, H., & Lastres-Becker, I. (2026). Summary of NRF2 implication in PD disease mouse models. Free Radical Biology and Medicine, 246, 760–779. https://doi.org/10.1016/j.freeradbiomed.2026.02.023
He, Y., Guo, L., Wang, L., Li, Z., Lu, R., Zhang, Q., & Xiong, K. (2026). Mitochondrial oxidative stress to PANoptosis: Current evidence and therapeutic implications for neurological diseases. Journal of Advanced Research. Advance online publication. https://doi.org/10.1016/j.jare.2026.02.023
Huang, J., & Li, W. (2024). Molecular crosstalk between circadian clock and NLRP3 inflammasome signaling in Parkinson's disease. Heliyon, 10(1), Article e24752. https://doi.org/10.1016/j.heliyon.2024.e24752
Jurado-Coronel, J., & Duennwald, M. L. (2026). Cannabidiol confers neuroprotection against 6-OHDA toxicity by rescuing Nrf2 proteostasis and preserving mitochondrial integrity. Free Radical Biology and Medicine, 255, 774–790. https://doi.org/10.1016/j.freeradbiomed.2026.08.012
Kamienieva, I., Charzynska, A., Duszynski, J., Malinska, D., & Szczepanowska, J. (2023). In search for mitochondrial biomarkers of Parkinson's disease: Findings in parkin-mutant human fibroblasts. Biochimica et Biophysica Acta – Molecular Basis of Disease, 1869(8), Article 166787. https://doi.org/10.1016/j.bbadis.2023.166787
Leites, E. P., & Morais, V. A. (2021). The PINK1-mediated crosstalk between neural cells and the underlying link to Parkinson's disease. Cells, 10(6), Article 1395. https://doi.org/10.3390/cells10061395
Liu, T., Wu, H., & Wei, J. (2026). Beyond the brain: Exploring the multi-organ axes in Parkinson's disease pathogenesis. Journal of Advanced Research, 80, 451–474. https://doi.org/10.1016/j.jare.2025.05.034
Panicker, N., Kam, T. I., Wang, H., Neifert, S., Chou, S. C., Kumar, M., … Dawson, T. M. (2022). Neuronal NLRP3 is a parkin substrate that drives neurodegeneration in Parkinson's disease. Neuron, 110(15), 2422–2437. https://doi.org/10.1016/j.neuron.2022.05.009
Pirooznia, S. K., Yuan, C., Khan, M. R., Karuppagounder, S. S., Wang, L., Xiong, Y., … Dawson, T. M. (2020). PARIS induced defects in mitochondrial biogenesis drive dopamine neuron loss under conditions of parkin or PINK1 deficiency. Molecular Neurodegeneration, 15, Article 29. https://doi.org/10.1186/s13024-020-00378-x
Pischedda, F., Piccoli, G., Rakovic, A., Klein, C., & Pichler, I. (2019). Parkin deficiency increases stress-induced translocation of AIF to the nucleus. International Journal of Molecular Sciences, 20(3), Article 748. https://doi.org/10.3390/ijms20030748
Ramírez-Carreto, R. J., Salas-Venegas, V., De la Rosa-Hernández, V., Medina-Campos, O. N., Martínez-Ortega, U., Torres-Guerrero, H., Hernández-Luis, F., Pedraza-Chaverri, J., Königsberg, M., & Chavarría, A. (2026). Silybin attenuates PERK/IRE1α ER-stress signaling, neuroinflammation, and restores CDNF levels in an MPTP-induced Parkinson's disease model. European Journal of Pharmacology, 1030, Article 179126. https://doi.org/10.1016/j.ejphar.2026.179126
Schapira, A. H., Cooper, J. M., Dexter, D., Jenner, P., Clark, J. B., & Marsden, C. D. (1989). Mitochondrial complex I deficiency in Parkinson's disease. The Lancet, 1(8649), 1269–1271. https://doi.org/10.1016/S0140-6736(89)92696-1
Shin, J. H., Ko, H. S., Kang, H., Lee, Y., Lee, Y. I., Pletinkova, O., … Dawson, T. M. (2011). PARIS (ZNF746) repression of PGC-1α contributes to neurodegeneration in Parkinson's disease. Cell, 144(5), 689–702. https://doi.org/10.1016/j.cell.2011.02.010
Spinazzola, A., & Zeviani, M. (2009). Mitochondrial diseases: A cross-talk between mitochondrial and nuclear genomes. Advances in Experimental Medicine and Biology, 652, 69–84. https://doi.org/10.1007/978-90-481-2913-3_6
Wang, Y., & Xia, Y. (2023). Astrocytic mitochondrial dysfunction and neuroinflammation in Parkinson's disease. Neurobiology of Disease, 184, Article 106224. https://doi.org/10.1016/j.nbd.2023.106224
Xu, L., Xiao, K., Jiang, J., Tang, Y., Yang, L., Xiao, S., Jin, X., Xiao, B., Zhou, T., Hao, C., Fan, H., & Chai, Z. (2026). Mechanism analysis of MPTP-induced Parkinson's disease-like pathology via the HPA axis–microglial glucocorticoid receptor pathway. Ecotoxicology and Environmental Safety, 323, Article 120715. https://doi.org/10.1016/j.ecoenv.2026.120715
Zhenxiong, Z. H. A. O., Mengdie, D. O. N. G., & Zhen, M. U. (2025). Gut-Brain Axis Dysregulation in Parkinson’s Disease: Mechanisms Linking Microbiota to Neuroinflammation and α-Synuclein Pathology. Journal of Pharmaceutical Analysis, 101521.