Mitochondrial fission factor regulates mitochondrial Ca2+ homeostasis and neuronal activity in AgRP neurons
Almudena Del Río-Martín1, Gagik Yeghiazaryan2, Rui de Oliveira Beleza1
1Department of Neuronal Control of Metabolism, Max Planck Institute for Metabolism Research, Gleueler Strasse 50, 50931 Cologne, Germany; Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD) and Center for Molecular Medicine Cologne (CMMC), University of Cologne, Joseph-Stelzmann-Strasse 26, 50931 Cologne, Germany; Policlinic for Endocrinology, Diabetes and Preventive Medicine (PEDP), University Hospital Cologne, Kerpener Strasse 26, 50924 Cologne, Germany.
Abstract:
Mitochondria represent central regulators of neuronal function, and their network is dynamically restructured via fission and fusion. The mitochondrial fission factor (MFF) serves as an adaptor protein that recruits and organizes the core fission machinery at the outer mitochondrial membrane. Here, we investigated the role of MFF in Agouti-related peptide (AgRP) neurons of the arcuate nucleus of the hypothalamus (ARC) in their regulation of systemic energy homeostasis. We demonstrated that mice lacking MFF in AgRP neurons exhibited increased mitochondrial size, both in AgRP neuron somata and their axonal compartments. This translated into increased mitochondrial Ca2+ uptake capacity, increased mitochondrial membrane potential, and a shift toward a more reduced mitochondrial NAD(P)H redox state. Ultimately, these changes resulted in increased neuronal excitability and neurotransmitter release to functionally enhance dynamic food intake during energy state transitions. Collectively, MFF-dependent mitochondrial fission links cell-type-specific neuronal mitochondrial dynamics via mitochondrial Ca2+ handling to control systemic metabolism.
Insights
Mitochondrial fission factor (MFF) controls mitochondrial dynamics in Agouti-related peptide (AgRP) neurons. Loss of MFF enhances neuronal excitability, impacting energy homeostasis and food intake regulation.
Area of Science:
- Neuroscience
- Cell Biology
- Metabolism
Background:
- Mitochondria are crucial for neuronal function, with their dynamics regulated by fission and fusion.
- Mitochondrial fission factor (MFF) organizes the mitochondrial fission machinery.
- Agouti-related peptide (AgRP) neurons in the hypothalamus regulate energy homeostasis.
Purpose of the Study:
- To investigate the role of MFF in AgRP neurons.
- To understand how MFF influences mitochondrial dynamics and neuronal function in energy regulation.
Main Methods:
- Mice with MFF deficiency specifically in AgRP neurons were utilized.
- Mitochondrial size, calcium uptake, membrane potential, and redox state were analyzed.
- Neuronal excitability and neurotransmitter release were assessed.
Main Results:
- Mice lacking MFF in AgRP neurons showed larger mitochondria.
- Mitochondrial Ca2+ uptake, membrane potential, and NAD(P)H redox state were altered.
- Increased neuronal excitability and neurotransmitter release were observed, enhancing food intake.
Conclusions:
- MFF-dependent mitochondrial fission is essential for regulating mitochondrial Ca2+ handling in AgRP neurons.
- Mitochondrial dynamics in AgRP neurons are linked to systemic energy homeostasis and metabolism.
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