The mitochondria are the powerhouse of the cell. It is also involved in other tasks, such as signaling, regulating cellular metabolism, and causing cell death.
In response to bioenergetic stress, mitochondria undergo fragmentation. Mitochondrial fission factor (MFF) promotes mitochondrial division by recruiting a secondary protein, DRP1, to the mitochondria. However, the precise molecular mechanisms underlying this recruitment and the overall process remain unclear.
Scientists at the University of Bristol have identified a key molecular step required to divide damaged mitochondria. The study could potentially establish how mitochondrial dysfunction goes wrong in common neurodegenerative diseases, such as Parkinson’s and Alzheimer’s.
The research team has identified mitochondrial fission factor (MFF) as a target for small ubiquitin-like modifier (SUMO) modifications, which are crucial for mitochondrial division. Their findings show that modified MFF does not act alone; it works alongside inhibitor proteins.
When mitochondria are damaged, SUMO modifies MFF, allowing it to release these inhibitors and bind to DRP1, facilitating division. Without SUMO modification, MFF cannot promote mitochondrial division in response to damage. This discovery enhances the team’s understanding of the intricate mechanisms governing mitochondrial division under stress.
Dr. Richard Seager, Research Associate in the School of Biochemistry at the University of Bristol and first author on the paper, said: “When we realized the previous model of how MFF and DRP1 support division did not fully agree with our findings, we investigated the mechanism differently, by looking at other protein players. This revealed a more complex pathway which brought together several previous models of how mitochondrial division works into one model, which is a very exciting finding.”
Jeremy Henley, Professor of Molecular Neuroscience in the School of Biochemistry and corresponding author, added, “Mitochondrial dynamics and the correct regulation of fusion and division are critical for cell health. This is highlighted by the fact that a number of human neurodegenerative diseases result from disruption in mitochondrial dynamics due to mutations in the proteins that perform fusion and division.”
“More common neurodegenerative diseases, such as Parkinson’s and Alzheimer’s, show mitochondrial dysfunction and often more fragmented mitochondria. Understanding the molecular details of mitochondrial division will allow researchers to know what might go wrong and possibly help prevent and treat diseases.”
The research primarily utilized non-neuronal cells, like immortalized fibroblasts, to uncover the molecular mechanisms of MFF-SUMO modification. Given that mitochondrial dysfunction is a key feature of neurodegenerative diseases, the team’s next phase involves studying MFF-SUMO in neuronal contexts.
They aim to explore how this modification affects mitochondrial morphology and function in neurons, the implications for neuronal behavior, and the critical connections between neurons, which depend on healthy mitochondria for energy.
Journal Reference:
- Richard Seager, Nitheyaa Shree Ramesh, Kevin A. Wilkinson, and Jeremy M. Henley et al. SUMOylation of MFF coordinates fission complexes to promote stress-induced mitochondrial fragmentation. Science Advances. DOI: 10.1126/sciadv.adq6223