Deep inside every cell, the nucleus is sealed by a double membrane pierced by large protein assemblies called nuclear pore complexes, each built from roughly thirty different proteins known as nucleoporins, or Nups. These structures are far more than passive holes in the nuclear envelope. They act as highly selective gatekeepers, controlling which proteins and RNA molecules move between the nucleus and the cytoplasm, and their integrity is essential for maintaining the distinct chemical identities of the two cellular compartments. When this trafficking system falters, transcription factors can become stranded in the wrong compartment, stress responses are blunted, and the genome becomes more vulnerable to damage, a cascade of consequences that is increasingly implicated in age-related neurodegenerative disorders.

The new study from the University of Georgia team adds an environmental dimension to this picture. Rather than focusing solely on genetic mutations, the researchers examined how mitochondrial toxicants, agents long associated with elevated Parkinson’s disease risk through epidemiological and experimental work, might damage the nuclear transport machinery itself. Their central finding is that when mitochondria in dopaminergic neurons are compromised, the nuclear pore complex does not simply weaken in a general sense. Instead, specific nucleoporins are selectively affected, suggesting a targeted and mechanistically specific form of damage rather than indiscriminate cellular breakdown.

Among the most consequential observations is the behavior of Nup62, a nucleoporin that normally resides in the central channel of the pore and forms the diffusion barrier regulating passive and facilitated transport. Under mitochondrial stress, Nup62 abandons its post at the nuclear envelope and accumulates in the cytoplasm. This mislocalization is significant because the central channel is where the actual traffic of molecules occurs. A channel protein drifting into the cytoplasm implies that the pore’s selective permeability barrier is physically compromised, potentially allowing molecules that should remain outside the nucleus to slip in, while simultaneously hindering the active, receptor-mediated transport of cargo that depends on intact pore architecture.

The study also documents losses in other structurally and functionally distinct pore components. Nup153 and Nup50, both associated with the nuclear basket, a filamentous structure extending from the pore into the nucleoplasm that helps dock and release transport cargo, show reduced expression. Nup107, a scaffold nucleoporin that forms part of the outer rings anchoring the entire complex to the nuclear membrane, is likewise diminished. This pattern matters because it suggests that mitochondrial dysfunction erodes the pore from multiple angles at once, degrading both the structural framework that holds the complex together and the functional elements that direct cargo through it.

Equally important is the disruption of the Ran GTPase system. Ran is a small signaling protein that exists in two states, bound to GTP in the nucleus and bound to GDP in the cytoplasm, and this asymmetric distribution, known as the Ran gradient, provides the directional energy that drives most nucleocytoplasmic transport. Transport receptors called karyopherins ferry cargo through the pore, and their ability to bind and release that cargo depends on which form of Ran they encounter. When the Ran gradient collapses, as the researchers observed in mitochondria-stressed dopaminergic neurons, the entire directional logic of nuclear transport breaks down. Cargo movement becomes disorganized, and the cell loses a fundamental layer of spatial regulation over its biochemistry.

The functional consequences were confirmed through transport assays showing that bidirectional movement of proteins across the nuclear envelope, both import into the nucleus and export back out to the cytoplasm, is impaired in dopaminergic neuronal cells subjected to mitochondrial stress. This bidirectional impairment is particularly damaging for neurons, which are long-lived, largely post-mitotic cells that cannot rely on cell division to dilute accumulated damage. Dopaminergic neurons of the substantia nigra, the population most affected in Parkinson’s disease, are already burdened by high oxidative metabolism, extensive branching, and dopamine chemistry that generates reactive species. Adding compromised nuclear transport to this list of vulnerabilities provides a plausible mechanism by which these cells cross the threshold into degeneration before others in the brain do.

A critical strength of the work is its translational reach. The researchers did not confine their findings to cell culture. Using brain tissue from individuals who had Parkinson’s disease, they identified abnormalities in nucleoporin pathology and loss of the Ran gradient within nigral dopaminergic neurons, the very cells that die in the disorder. This convergence between experimentally induced mitochondrial dysfunction in model systems and pathology observed in human tissue substantially strengthens the argument that nuclear pore impairment is not an artifact of the laboratory but a feature of the disease itself.

The environmental connection deserves emphasis. Epidemiological studies have repeatedly linked exposure to certain pesticides and other mitochondrial toxicants with increased Parkinson’s disease risk, and classic experimental models of parkinsonism, such as those induced by complex I inhibitors, are built on mitochondrial poisoning. What has remained less clear is the sequence of events connecting mitochondrial damage to the death of dopaminergic neurons. This study proposes a specific intermediate step: mitochondrial dysfunction disrupts the nuclear pore complex and the transport processes it mediates, and this disruption contributes to neurodegeneration. If correct, it means that some of the neuronal damage wrought by environmental exposures may be mediated through a previously underappreciated route, one that operates at the level of nuclear-cytoplasmic compartmentalization rather than through energy failure or oxidative damage alone.

The findings also connect to a broader body of literature on nuclear transport defects in neurodegeneration. Abnormalities in nucleoporins and in the Ran system have been reported in other neurological conditions, and the nuclear envelope itself has been observed to assume abnormal shapes in affected dopaminergic neurons in Parkinson’s disease. Mislocalized transcription factors, another hallmark noted in the disease, fit naturally into this framework, since transcription factors are classic cargo of the nuclear transport system. When pores and gradients fail, transcriptional programs that depend on precisely timed nuclear entry of regulatory proteins fall out of sync, potentially compounding the stress on vulnerable neurons.

From a research methodology standpoint, the study’s use of both in vitro and in vivo dopaminergic neuron models of mitochondrial dysfunction allows the authors to demonstrate that Nup abnormalities are reproducible across experimental contexts, while the human brain data anchor the work in clinical reality. The identification of specific nucleoporins, rather than a vague statement about pore damage, also opens the door to more targeted future investigations. Researchers can now ask, for example, whether preserving Nup62 localization or maintaining the Ran gradient can protect dopaminergic neurons from mitochondrial stress, questions that could eventually inform therapeutic strategies aimed at shoring up nuclear transport in at-risk cells.

There are also implications for how environmental risk is understood more broadly. If mitochondrial toxicants damage the nuclear pore complex, then the cellular consequences of exposure may extend well beyond the period of acute mitochondrial impairment. Nuclear pores are large, complex assemblies whose maintenance depends on ongoing protein quality control and turnover. Damage to their components could persist and accumulate over time, providing a mechanism by which transient or low-level environmental exposures might contribute to the slow, decades-long trajectory of neurodegeneration characteristic of Parkinson’s disease. This temporal amplification, in which a relatively brief insult leaves a lasting mark on a critical cellular infrastructure, is an area that future work will need to explore in detail.

The study was supported by funding from the National Institutes of Health, including grants R01 ES027245, R01 ES034196, and R01 NS121692, along with the Johnny Isakson Endowment and the Coach Mark Richt Neurological Disease Research Fund. The work was carried out at the Isakson Center for Neurological Disease Research in the Department of Physiology and Pharmacology at the University of Georgia, with microscopy support from the institution’s Biomedical Microscopy Core and Georgia Electron Microscopy facilities. The research team, led by Zainab Riaz and colleagues under the senior authorship of Anumantha G. Kanthasamy, reports no competing financial interests related to the findings. As an open-access publication in npj Parkinson’s Disease, the full dataset and methods are available to the research community, enabling replication and extension of these observations as the field works to determine whether protecting the nuclear pore complex can slow the progression of environmentally linked Parkinson’s disease.

Subject of Research: Neuroscience

Article Title: Environmental neurotoxicant-induced mitochondrial dysfunction impairs the nuclear pore complex and nucleocytoplasmic transport in Parkinson’s disease pathogenesis

Article References: Riaz, Z., Chang, Y.-T., Jang, A., Richardson, G. S., Samidurai, M., Zenitsky, G., Jin, H., Anantharam, V., Kanthasamy, A., & Kanthasamy, A. G. (2026). Environmental neurotoxicant-induced mitochondrial dysfunction impairs the nuclear pore complex and nucleocytoplasmic transport in Parkinson’s disease pathogenesis. npj Parkinson's Disease. https://doi.org/10.1038/s41531-026-01553-y

Image Credits: AI Generated

DOI: 10.1038/s41531-026-01553-y

Keywords: Parkinson's disease, nuclear pore complex, nucleocytoplasmic transport, mitochondrial dysfunction, environmental neurotoxicants, nucleoporins, dopaminergic neurons, Ran GTPase, Nup62, neurodegeneration, Environmental, neurotoxicant-induced