Volume 10 Number 1 2026
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) 1-8 https://doi.org/10.25163/biomedical.10110926
Submitted: 21 July 2026 Revised: 12 September 2026 Accepted: 22 September 2026 Published: 24 September 2026
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
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