A new study revealed how a mutation in Valosin-containing protein, linked to both amyotrophic lateral sclerosis and frontotemporal dementia, could alter mitochondrial function, potentially contributing to the progression of these neurodegenerative diseases.

In the study, published in Acta Neuropathologica Communications, researchers used a CRISPR/Cas9-engineered cell model to find that this mutation leads to mitochondrial hypermetabolism, providing key insights into disease mechanisms.

Valosin-containing protein (VCP) plays critical roles in cellular processes such as protein degradation, organelle maintenance, and DNA repair. Mutations in VCP are associated with multisystem proteinopathy (MSP1), a rare disorder that impacts muscle, brain, and bone. Notably, up to 10% of VCP mutation carriers develop amyotrophic lateral sclerosis (ALS), while about 30% develop frontotemporal dementia (FTD).

The study focused on a specific mutation, VCP^R191Q/wt, using a neuroblastoma cell line to investigate its impact on mitochondria. Mitochondria in the mutated cells were found to be enlarged, with a depolarized membrane potential. Increased activity in the electron transport chain (ETC) and elevated respiration rates indicated mitochondrial hypermetabolism. One of the key findings of the study was that the mutation caused an increased opening of the mitochondrial permeability transition pore (mPTP), a channel involved in mitochondrial function, leading to mild mitochondrial uncoupling.

The study suggested that this mitochondrial hyperactivity could partly be driven by calcium overload, which triggers the opening of the mPTP. These changes can disrupt mitochondrial homeostasis, potentially accelerating neurodegeneration. As mitochondria are essential for meeting neurons' high energy demands, dysfunction in these organelles could contribute to the neurodegenerative processes in ALS and FTD.

The findings provided new evidence supporting the role of mitochondrial dysfunction in these diseases and highlighted the potential of targeting mitochondrial pathways as part of future therapeutic strategies. Understanding how the VCP mutation alters mitochondrial bioenergetics could pave the way for treatments that prevent or mitigate the progression of ALS and FTD.

Conflict of interest disclosure can be found in the study.