Mitochondrial calcium cycling in neuronal function and neurodegeneration.

Mitochondria are essential for proper cellular function through their critical roles in ATP synthesis, reactive oxygen species production, calcium (Ca) buffering, and apoptotic signaling. In neurons, Ca buffering is particularly important as it helps to shape Ca signals and to regulate numerous Ca-dependent functions including neuronal excitability, synaptic transmission, gene expression, and neuronal toxicity. Over the past decade, identification of the mitochondrial Ca uniporter (MCU) and other molecular components of mitochondrial Ca transport has provided insight into the roles that mitochondrial Ca regulation plays in neuronal function in health and disease.

MCU (mitochondrial Ca uniporter) makes the calcium go round.

Store-operated Ca entry (SOCE) is a major mechanism controlling Ca signaling and Ca-dependent functions and has been implicated in immunity, cancer, and organ development. SOCE-dependent cytosolic Ca signals are affected by mitochondrial Ca transport through several competing mechanisms. However, how these mechanisms interact in shaping Ca dynamics and regulating Ca-dependent functions remains unclear.

Distinct properties of Ca efflux from brain, heart and liver mitochondria: The effects of Na, Li and the mitochondrial Na/Ca exchange inhibitor CGP37157.

Mitochondrial Ca transport is essential for regulating cell bioenergetics, Ca signaling and cell death. Mitochondria accumulate Ca via the mitochondrial Ca uniporter (MCU), whereas Ca is extruded by the mitochondrial Na/Ca (mtNCX) and H/Ca exchangers. The balance between these processes is essential for preventing toxic mitochondrial Ca overload.

FGF21 Signals to Glutamatergic Neurons in the Ventromedial Hypothalamus to Suppress Carbohydrate Intake.

Fibroblast growth factor 21 (FGF21) is an endocrine hormone produced by the liver that regulates nutrient and metabolic homeostasis. FGF21 production is increased in response to macronutrient imbalance and signals to the brain to suppress sugar intake and sweet-taste preference. However, the central targets mediating these effects have been unclear.

Deletion of a Neuronal Drp1 Activator Protects against Cerebral Ischemia.

Mitochondrial fission catalyzed by dynamin-related protein 1 (Drp1) is necessary for mitochondrial biogenesis and maintenance of healthy mitochondria. However, excessive fission has been associated with multiple neurodegenerative disorders, and we recently reported that mice with smaller mitochondria are sensitized to ischemic stroke injury. Although pharmacological Drp1 inhibition has been put forward as neuroprotective, the specificity and mechanism of the inhibitor used is controversial.