Mitochondria in Neuroplasticity and Neurological Disorders

Abstract

Mitochondrial electron transport generates the ATP that is essential for the excitability and survival of neurons, and the protein phosphorylation reactions that mediate synaptic signaling and related long-term changes in neuronal structure and function. Mitochondria are highly dynamic organelles that divide, fuse and move purposefully within axons and dendrites. An Major functions of mitochondria in neurons include the regulation of Ca2+ and redox signaling, developmental and synaptic plasticity, and the arbitration of cell survival and death. The importance of mitochondria in neurons is evident in the neurological phenotypes in rare diseases caused by mutations in mitochondrial genes. Mitochondria-mediated oxidative stress, perturbed Ca2+ homeostasis and apoptosis may also contribute to the pathogenesis of prominent neurological diseases including Alzheimer’s, Parkinson’s and Huntington’s diseases, stroke, ALS and psychiatric disorders. Advances in understanding the molecular and cell biology of mitochondria are leading to novel approaches for the prevention and treatment of neurological disorders.

Intracellular ASIC1a regulates mitochondrial permeability transition-dependent neuronal death

“…On the contrary, mitochondrial dysfunction (such as energy failure and alteration of mitochondrial ROS production) is generally accepted as a prominent cause of axonal degeneration in multiple sclerosis, and two inhibitors of MPT pore formation have been shown to delay disease onset and increase survival of amyotrophic lateral sclerosis mice. 13,46 Because mitochondria (and presumably mtASIC1a) are distributed and functional in axons, 13 our study provides an alternative explanation that the protection against axonal degeneration observed in ASIC1a-deficient mice may be due to reduced activity in MPT. Taken together, our findings suggest that, besides plasma membrane ASIC1a, mtASIC1a may also be a promising target for drug design and clinical therapy.…”

“…10,14,17 Therefore, although speculative, plasma membrane ASIC1a (death initiator) and mtASIC1a (death executor) may function at different levels to regulate ischemic cell death, which may cooperatively explain the observed strong neuroprotective effect in ASIC1a-knockout mice (Figure 6b). 10,13,15 It was reported that compared with WT mice, ASIC1a-deficient mice had both a markedly reduced motor deficit and decreased axonal degeneration in a mouse model of experimental autoimmune encephalomyelitis despite the similar levels of CNS inflammation. 39,43 Interestingly, ASIC1a was found only in the surface membrane of neuronal soma and dendrites but not that of axons.…”

“…13 Mitochondrial permeability transition (MPT) is a key event that occurs in most forms of cell demise (apoptotic, necrotic, autophagic or mitotic), determining the life and death of cells. [14][15][16] The opening of MPT pores causes an abrupt increase of inner mitochondrial membrane permeability to solutes with molecular masses of o1500 Da, 14,16,17 leading to mitochondrial swelling, disruption of the mitochondrial outer membranes and mitochondrial dysfunction.…”

“…These conditions increase mitochondrial susceptibility to MPT. 10,13,14,16 Upon reperfusion, the MPT pores finally open, leading to ischemic/ reperfusion neuronal death. Moreover, deletion of cyclophilin D (CypD), a key regulator of the MPT pore, effectively rescued the ischemic damage.…”

Intragenic deletions affecting two alternative transcripts of the IMMP2L gene in patients with Tourette syndrome

“…16 Incomplete processing of IMMP2L substrates seems to result in a hyperactive mitochondrion with an increased production of superoxide 16 and to promote the formation of a mitochondrial permeability transition pore which leads to release of pro-apoptotic proteins, and thereby activating cell death pathways. 17,18 In this study, we describe seven Danish TS patients with intragenic IMMP2L deletions, affecting one of two alternative IMMP2L transcripts (the previously described long transcript and a short alternative transcript with the two first exons residing within intron 3 of the long transcript). The deletions are significantly more frequent in the patients compared with the controls giving further evidence for IMMP2L as a TS susceptibility gene.…”