Mitochondrial calcium homeostasis: Implications for neurovascular and neurometabolic coupling

Abstract

Mitochondrial function is critical to maintain high rates of oxidative metabolism supporting energy demands of both spontaneous and evoked neuronal activity in the brain. Mitochondria not only regulate energy metabolism, but also influence neuronal signaling. Regulation of ''energy metabolism'' and ''neuronal signaling'' (i.e. neurometabolic coupling), which are coupled rather than independent can be understood through mitochondria's integrative functions of calcium ion (Ca 2þ ) uptake and cycling. While mitochondrial Ca 2þ do not affect hemodynamics directly, neuronal activity changes are mechanistically linked to functional hyperemic responses (i.e. neurovascular coupling). Early in vitro studies lay the foundation of mitochondrial Ca 2þ homeostasis and its functional roles within cells. However, recent in vivo approaches indicate mitochondrial Ca 2þ homeostasis as maintained by the role of mitochondrial Ca 2þ uniporter (mCU) influences system-level brain activity as measured by a variety of techniques. Based on earlier evidence of subcellular cytoplasmic Ca 2þ microdomains and cellular bioenergetic states, a mechanistic model of Ca 2þ mobilization is presented to understand systems-level neurovascular and neurometabolic coupling. This integrated view from molecular and cellular to the systems level, where mCU plays a major role in mitochondrial and cellular Ca 2þ homeostasis, may explain the wide range of activation-induced coupling across neuronal activity, hemodynamic, and metabolic responses.

Bioenergetic Mechanisms of Seizure Control

“…The “push” mechanisms, such as the mitochondrial Ca 2+ -cycle, are complementary in regulating energy metabolism ( Kovács et al, 2005 ; Wei et al, 2011 ; Berndt et al, 2015 ; Nicholls, 2017 ; Kannurpatti, 2017 ). Neuronal firing and synaptic activity results in localized transient cytoplasmic Ca 2+ increases, which are sequestered by mitochondria via the mitochondrial Ca 2+ uniporter (MCU) channel complex leading to increased matrix Ca 2+ concentration.…”

Fusion or Fission: The Destiny of Mitochondria In Traumatic Brain Injury of Different Severities

“…The crucial role of mitochondria to maintain cell life has become more evident over the last few decades. Physiologically, these organelles are involved in many key cellular processes including being responsible for the supply of energy (which is produced by the electron transport chain coupled to oxidative phosphorylation and ATP production), to act as an effective storage for calcium ions and to actively participate in intracellular trafficking 1 . Pathologically, mitochondria are involved in the generation of the so-called oxidative/nitrosative stress, caused by excess production of reactive oxygen and nitrogen species (ROS and RNS, respectively), as well as in the induction of apoptosis 2 , 3 .…”

Calibrated imaging reveals altered grey matter metabolism related to white matter microstructure and symptom severity in multiple sclerosis

“…Because metabolic substrate and mitochondrial production are largely supported by the cell bodies [see MacAskill and Kittler, ], this increase in energetic burden for white matter related to its extent of damage, would weigh heavily upon the grey matter. Increased burden on grey matter, coupled with decreased transport of metabolic substrate [see Paling et al, ], probably results in decreases in basal levels of neurometabolism [for work on mitochondrial inhibition and neuroimaging see Kannurpati, ; Sanganahalli et al, ]. For example, negative relationships have been observed between basal NAA:creatine ratios and RD in MS white matter [Hannoun et al, ; see also Kahn et al, ].…”