Chenna, S. | bioRxiv Science

bioRxiv2025

Integrating simulated and experimental data to identify mitochondrial bioenergetic defects in Parkinson's Disease models

Mitochondrial bioenergetics are vital for ATP production and are associated with several diseases, including Parkinsons Disease. 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 respiratory chain 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 Parkinsons Disease models. We verified that the impaired bioenergetic profile previously measured in Parkin knockout neurons can be explained by increased mitochondrial uncoupling. We then generated primary cortical neurons from a Pink1 KO mouse model of Parkinsons, and measured reduced OCR capacity and increased resistance to Complex III inhibition. Here, our pipeline predicted that multiple respiratory chain 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. HighlightsO_LIThe complexity of mitochondrial bioenergetics can make experimental data difficult to interpret. C_LIO_LIWe simulated a computational model of mitochondrial bioenergetics in healthy and pathological conditions, and established an analysis pipeline to integrate model simulations with experimental data. C_LIO_LIWe applied the pipeline to data from Parkinsons Disease models to predict the molecular defects underlying Parkinsons-related pathology. C_LIO_LIWe provide all outputs in a user-friendly Excel file, which serves as a valuable resource to the community for insight into the effects of pathology on mitochondrial bioenergetics and for interpretation of experimental results. C_LI

neuroscience↗

bioRxiv2025

Copper-sensitive OsSPL9 TF regulates expression of indica rice domestication-associated miRNAs and phenotypes

Domestication of indica rice facilitated better harvest and yield, however the molecular mechanisms that drove multitude of the associated phenotypes is poorly understood. A few genetic and epigenetic mechanisms have been attributed to indica rice domestication; however, upstream regulators of these variations are unknown. Here, we identified a copper (Cu)-dependent regulatory module, involved in the regulation of OsSPL9 TF and two classes of RNAs under its control. Differential accumulation of Cu-associated micro(mi)RNAs and Cu-associated protein-coding RNAs were a major portion of the differences between wild (Oryza nivara) and cultivated rice lines. We identified OsSPL9 as an upstream regulator of these changes through genetic and molecular analysis as well as by using Cu stressed conditions. OsSPL9 bound to the promoters of these genes through a conserved GTAC enriched motif. OsSPL9, Cu-associated miRNAs and their targets acted as a regulatory loop, since mis-expression of SPL9 alone, or any individual Cu-associated miRNA, also altered levels of other Cu-miRNAs and their cognate targets. OsSPL9-mediated regulation was closely linked to Cu accumulation and metabolism, indicating previously unappreciated roles of metal ions in mediating domestication-associated phenotypes. Our study facilitates a better understanding of the crosstalk between genetic and epigenetic regulation that contributed to indica rice domestication.

plant biology↗