Mitochondrial Proteins Linked to PD and ALS Safeguard Brain Lipid Balance and Stress Response
A new study, published in Cell Death & Disease, led by Dr. Roberta Filograna’s team at MBB, reveals how the mitochondrial proteins CHCHD2 and CHCHD10 help maintain brain lipid balance and protect against mitochondrial stress. Previously associated with genetic forms of Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS), these proteins play key roles in preserving neuronal health. The findings provide new insight into how their dysfunction contributes to neurodegeneration.
The researchers found that CHCHD2 and CHCHD10 form a mitochondrial complex essential for maintaining lipid metabolism and mitochondrial function. Male mice lacking CHCHD2 developed age-related motor impairments and dopamine depletion, while females were less affected. Despite normal mitochondrial structure and energy production, affected brains showed distinct lipid alterations, particularly in sphingolipids and phosphatidylcholines—molecules critical for neuronal signaling and function.
“Our study reveals that the CHCHD2–CHCHD10 complex links mitochondrial health to brain lipid metabolism. When mitochondria are stressed, both proteins and their complex increase in abundance and size, suggesting they act as part of the cell’s defense system. Disruptions in this pathway may render neurons more vulnerable to degeneration.”, says Dr. Roberta Filograna.
Mutations in CHCHD2 and CHCHD10 have been identified in PD, ALS, and frontotemporal dementia, directly linking mitochondrial dysfunction to age-related neurodegenerative diseases. Understanding how this complex preserves mitochondrial and lipid integrity could inform new strategies to enhance neuronal resilience.
To uncover these mechanisms, the team combined genetic mouse models, cell-based experiments, and advanced biochemical and imaging techniques, including MALDI-based lipidomics and complexome profiling, to characterize the CHCHD2–CHCHD10 complex and its response to mitochondrial stress.
As the burden of neurodegenerative disease continues to grow, these findings bring researchers closer to understanding and potentially counteracting how mitochondrial failure drives neuronal decline.
Publication
The CHCHD2-CHCHD10 protein complex is modulated by mitochondrial dysfunction and alters lipid homeostasis in the mouse brain.
Gerlach J, Pireddu P, Zhang X, Wetzel S, Mennuni M, Milenkovic D, Nolte H, da Silva Rodrigues F, Branzell N, Kaya I, Villegas RG, Rubalcava-Gracia D, Alsina D, Feederle R, Andrén PE, Langer T, Svenningsson P, Filograna R
Cell Death Dis 2025 Oct;16(1):693