TY  - JOUR
AU  - Chenna, Sandeep
AU  - Joselin, Alvin
AU  - Theurey, Pierre
AU  - Bano, Daniele
AU  - Pizzo, Paola
AU  - Ankarcrona, Maria
AU  - Park, David S
AU  - Prehn, Jochen H
AU  - Connolly, Niamh M C
TI  - Integrating simulated and experimental data to identify mitochondrial bioenergetic defects in Parkinson's Disease models.
JO  - PLOS ONE
VL  - 21
IS  - 1
SN  - 1932-6203
CY  - San Francisco, California, US
PB  - PLOS
M1  - DZNE-2026-00040
SP  - e0339326
PY  - 2026
AB  - Mitochondrial bioenergetics are vital for ATP production and are associated with several diseases, including Parkinson's Disease (PD). Here, we simulated a computational model of mitochondrial ATP production to interrogate mitochondrial bioenergetics under physiological and pathophysiological conditions, and provide a data resource that can be used to interpret mitochondrial bioenergetics experiments. We first characterised the impact of several common electron transport chain (ETC) impairments on experimentally-observable bioenergetic parameters. We then established an analysis pipeline to integrate simulations with experimental data and predict the molecular defects underlying experimental bioenergetic phenotypes. We applied the pipeline to data from PD models. We verified that the impaired bioenergetic profile previously measured in Parkin knockout (KO) neurons can be explained by increased mitochondrial uncoupling. We then generated primary cortical neurons from a Pink1 KO mouse model of PD, and measured reduced oxygen consumption rate (OCR) capacity and increased resistance to Complex III inhibition. Here, our pipeline predicted that multiple impairments are required to explain this bioenergetic phenotype. Finally, we provide all simulated data as a user-friendly resource that can be used to interpret mitochondrial bioenergetics experiments, predict underlying molecular defects, and inform experimental design.
KW  - Animals
KW  - Mitochondria: metabolism
KW  - Mitochondria: pathology
KW  - Parkinson Disease: metabolism
KW  - Parkinson Disease: pathology
KW  - Parkinson Disease: genetics
KW  - Energy Metabolism
KW  - Mice
KW  - Disease Models, Animal
KW  - Neurons: metabolism
KW  - Neurons: pathology
KW  - Mice, Knockout
KW  - Computer Simulation
KW  - Oxygen Consumption
KW  - Ubiquitin-Protein Ligases: genetics
KW  - Ubiquitin-Protein Ligases: metabolism
KW  - Protein Kinases: genetics
KW  - Protein Kinases: metabolism
KW  - Adenosine Triphosphate: metabolism
KW  - Adenosine Triphosphate: biosynthesis
KW  - Humans
KW  - PTEN-induced putative kinase (NLM Chemicals)
KW  - Ubiquitin-Protein Ligases (NLM Chemicals)
KW  - Protein Kinases (NLM Chemicals)
KW  - Adenosine Triphosphate (NLM Chemicals)
KW  - parkin protein (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:41490258
DO  - DOI:10.1371/journal.pone.0339326
UR  - https://pub.dzne.de/record/283144
ER  -