Parkinson’s disease ranks as the second most prevalent neurodegenerative condition, impacting more than 10 million individuals globally. Certain variations of Parkinson’s are marked by an inability of cells to eliminate dysfunctional mitochondria, the energy “centers” of the cells, especially in the neural cells of the brain. Similar to batteries, mitochondria provide energy necessary for cellular operations, but, analogous to batteries, they can also leak harmful substances as they deteriorate. Mitophagy is the mechanism through which cells perform quality control by disposing of aged and faulty mitochondria, akin to discarding trash.
Recently, research from Caltech indicates that two potential drugs aimed at activating mitophagy do not work as intended to lessen Parkinson’s symptoms; rather, they merely harm cells.
The findings are presented in a paper published in Science Advances on August 27. This investigation was spearheaded by former graduate student William Rosencrans (PhD ’25) and represents a partnership between the labs of Tsui-Fen Chou, research professor of biology and biological engineering, and David Chan, Harold and Violet Alvarez Professor of Biology and dean of graduate studies.
Two genes primarily drive the initiation of mitophagy: PINK1 and PARKIN. Investigators have sought to formulate medications that assist cells in activating these pathways, particularly with the aim of treating individuals with Parkinson’s disease. However, the recent study reveals that two of these drug candidates trigger mitophagy by damaging healthy mitochondria instead of properly activating the intended pathways.
“Envision your microwave is malfunctioning, and instead of calling your waste collector to discard it, you pulverized it further with a sledgehammer,” says Rosencrans. “That would compel you to get rid of it, but it’s not our goal for drugs to harm our cells in such a manner.”
Throughout the study, the team recognized that the conventional assay used to screen drugs for mitophagy induction lacks the precision necessary to ascertain the actual effects of the drug on the cell. These tests are performed on healthy cells with functioning mitophagy pathways; these can be inadvertently activated by drugs that stress and damage the mitochondria, potentially misleading researchers into identifying mitochondrial toxins rather than advantageous drugs that promote mitophagy pathways.
Besides Parkinson’s disease, numerous other neurodegenerative disorders face mitochondrial quality-control challenges. The team is presently engaged in creating a new class of medications that stimulate mitophagy without inflicting damage on mitochondria.
“Billions of dollars are allocated to drug development, and this underscores the importance of utilizing our federal funding to comprehend the mechanisms driving drug efficacy to enhance existing treatments and innovate new ones,” Rosencrans explains. “Conducting fundamental research into how these processes operate is crucial.”
The paper is titled “Putative PINK1/PARKIN Activators Lower the Threshold for Mitophagy by Sensitizing Cells to Mitochondrial Stress.” Apart from Rosencrans (currently a post-doctoral scholar at the National Institute of Neurological Disorders and Stroke), Ryan W. Lee serves as co-first author. Additional Caltech co-authors include former graduate student Logan McGraw (MS ’24), incoming graduate student Ian Horsburgh, staff scientists Ting-Yu Wang and Baiyi Quan, and research technician-assistant Diana Huynh. Former Caltech postdoctoral scholar Jennifer A. Johnston, who is now the founder and CEO of NysnoBio, is also a co-author. Financial support came from the National Institute of Neurological Disorders and Stroke, the Center for Alzheimer’s and Related Dementias, the National Institutes of Health, the Merkin Institute for Translational Research at Caltech, and the Michael J. Fox Foundation. Tsui-Fen Chou and David Chan are affiliated faculty members with the Tianqiao and Chrissy Chen Institute for Neuroscience at Caltech.