Open Access

REVIEW

Mitochondrial Dysfunction in Parkinson’s Disease: Is Impaired Deuterium Depleted Nutrient Supply by Gut Microbes a Primary Factor?

Stephanie Seneff^1,*, Greg Nigh², Anthony M. Kyriakopoulos^3,4

1 Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
2Private Practice, Greg Nigh, LLC, Westerly, RI 02891, USA
3 Laboratory of Molecular Biology and Immunology, Department of Pharmacy, University of Patras, Rio-Patras, 26500, Greece
4 Department of Research and Development, Nasco AD Biotechnology Laboratory, Piraeus, 18536, Greece

* Corresponding Author: Stephanie Seneff. Email:

(This article belongs to the Special Issue: Cellular Mechanisms and Therapeutic Approaches in Protein Misfolding Diseases)

BIOCELL 2025, 49(9), 1545-1572. https://doi.org/10.32604/biocell.2025.066687

Received 15 April 2025; Accepted 10 June 2025; Issue published 25 September 2025

Abstract

Deuterium is a heavy isotope of hydrogen, with an extra neutron, endowing it with unique biophysical and biochemical properties compared to hydrogen. The ATPase pumps in the mitochondria depend upon proton motive force to catalyze the reaction that produces ATP. Deuterons disrupt the pumps, inducing excessive reactive oxygen species and decreased ATP synthesis. The aim of this review is to develop a theory that mitochondrial dysfunction due to deuterium overload, systemically, is a primary cause of Parkinson’s disease (PD). The gut microbes supply deuterium-depleted short chain fatty acids (SCFAs) to the colonocytes, particularly butyrate, and an insufficient supply of butyrate may be a primary driver behind mitochondrial dysfunction in the gut, an early factor in PD. Indeed, low gut butyrate is a characteristic feature of PD. Mitochondrial dysfunction is a factor in many diseases, including all neurodegenerative diseases. Biological organisms have devised sophisticated strategies for protecting the ATPase pumps from deuterium overload. One such strategy may involve capturing deuterons in bis-allylic carbon atoms present in polyunsaturated fatty acids (PUFAs) in cardiolipin. Cardiolipin uniquely localizes to the inner membrane of the intermembrane space, tightly integrated into ATPase proteins. Bis-allylic carbon atoms can capture and retain deuterium, and, interestingly, deuterium doping in PUFAs can quench the chain reaction that causes massive damage upon lipid peroxidation. Neuronal cardiolipin is especially rich in docosahexaenoic acid (DHA), a PUFA with five bis-allylic carbon atoms. Upon excessive oxidative stress, cardiolipin migrates to the outer membrane, where it interacts with α-synuclein (α-syn), the amyloidogenic protein that accumulates as fibrils in Lewy bodies in association with PD. Such interaction leads to pore formation and the launch of an apoptotic cascade. α-syn misfolding likely begins in the gut, and misfolded α-syn travels along nerve fibers, particularly the vagus nerve, to reach the brainstem nuclei, where it can seed misfolding of α-syn molecules already present there. Mitochondrial dysfunction in the gut may be a primary factor in PD, and low-deuterium nutrients may be therapeutic.

---

Keywords

---