Mitochondrial transport and energy metabolism in synaptic transmission and neuronal degeneration and regeneration

National Institute Of Neurological Disorders And Stroke

Investigators

Linked publications & trials

Abstract

Accomplishment 1. Reveal an energy signaling pathway that recruits and captures presynaptic mitochondria to sustain synaptic efficacy (Li et al., Nature Metabolism 2020) Presynaptic mitochondria play an essential role in maintaining effective synaptic transmission by generating ATP and sequestering presynaptic Ca2+. A brief interruption in local ATP synthesis or depletion of presynaptic mitochondria compromises synaptic transmission. However, only 33% of presynaptic terminals retain mitochondria, and as such sustained synaptic activity is restricted within mitochondria-containing synapses. Therefore, revealing mechanisms for recruiting and retaining presynaptic mitochondria will advance our knowledge of how neurons sustain synaptic efficacy and long-term synaptic plasticity. In this study, we reveal a mechanistic crosstalk between presynaptic energy sensing and mitochondrial anchoring. Sustained synaptic activity induces presynaptic energy deficits, a phenotype that could be rescued by recruiting mitochondria through an AMPK-PAK energy signaling pathway. Axonal mitochondria are captured at presynaptic terminals via an interplay between myosin VI (myo6) and SNPH. Synaptic activity activates AMPK-PAK signaling that mediates myo6 phosphorylation and drives mitochondria to presynaptic terminals and be anchored on F-actin. This pathway maintains presynaptic ATP supply during intensive synaptic activity. Disrupting this signaling crosstalk triggers local energy deficits and Ca2+ buildup, leading to impaired synaptic efficacy during trains of stimulation, and reduced recovery from synaptic depression after prolonged synaptic activity. Our study reveals an energy-sensitive capture of presynaptic mitochondria, which fine-tunes short-term synaptic plasticity and maintains prolonged synaptic efficacy. Accomplishment 2. Promoting CNS regeneration after spinal cord injuries by targeting mitochondrial anchor SNPH (Han et al., Cell Metabolism 2020) Mature CNS neurons typically fail to regrow after injury due to an intrinsic decline of permissive conditions. Regeneration requires a high level of energy consumption. This is particularly problematic in spinal cord injury (SCI) that damages mitochondria, leading to a local energy crisis in long-projection cortico-spinal tract (CST) axons. We hypothesize that injury-induced mitochondrial damage contributes to the intrinsic energetic restriction that accounts for regeneration failure in the CNS. Enhancing mitochondrial transport not only removes those damaged mitochondria, but also replenish healthy ones to power regenerative events. To test our hypothesis, we collaborated with Dr. Xiao-Ming Xu's lab (Indiana University) by using three SCI models in snph -/- mice, in which axonal mitochondrial transport is robustly increased. We demonstrate that snph-/- mice display enhanced CST axon regeneration passing through the lesion, accelerated regrowth of monoaminergic axons across a transection gap, and increased compensatory sprouting of uninjured CST. Enhancing mitochondrial transport facilitates the delivery of healthy mitochondria from the motor cortex into the regenerating CST axons, which form cortico-spinal motor synapses. The snph-/- mice display notable forelimb dexterous improvement after the C5 SCI. Our energy crisis model is further tested by the finding that systemic administration of creatine, a bioenergetic compound, facilitates CST axonal regeneration. Thus, repairing energy supply by enhancing mitochondrial transport or boosting cellular energetics is a promising strategy to promote axonal regeneration and functional restoration after CNS injuries. Accomplishment 3. Reprogramming an energetic AKT-PAK5 axis boosts axon energy supply and facilitates neuron survival and regeneration after injury-ischemia (Huang et al., Current Biology 2021) Mitochondrial dysfunction and energy crisis are the hallmarks of ischemic injury that typically leads to the cell death within affected brain region. Mitochondrial bioenergetics in an ischemic region are directly affected by impaired delivery of glucose and oxygen, and further damaged by altered mitochondrial structures, dynamics and transport. In mature neurons, axonal mitochondrial integrity, content, and ATP levels were reduced after oxygen and glucose deprivation and reperfusion, leading to axonal degeneration. To survive an ischemic injury, neurons require high levels of energy consumption. In adult brains, highly enriched SNPH expression results in the vast majority of axonal mitochondria remaining stationary. In addition, ATP has a limited diffusion capacity within long axons. These extrinsic insults and intrinsic restrictions lead to an energy crisis in injured axons. In this study, we elucidate an intrinsic energetic repair signaling axis that boosts axonal energy supply by reprogramming mitochondrial trafficking and anchoring in response to acute injury-ischemic stress in mature neurons and adult brains. PAK5 is a brain mitochondrial kinase with declined expression in mature neurons. PAK5 synthesis and signaling is spatiotemporally activated within axons in response to ischemic stress and axonal injury. PAK5 signaling remobilizes and replaces damaged mitochondria via the phosphorylation switch that turns off the axonal mitochondrial anchor SNPH. Injury-ischemic insults trigger AKT growth signaling that activates PAK5 and boosts local energy supply, thus protecting axon survival and facilitating regeneration in in vitro and in vivo models. Thus, our study reveals an axonal mitochondrial signaling axis that responds to injury and ischemia. While cell-to-cell mitochondrial transfer has surfaced as a possible avenue for brain injury and stroke, reprogramming an enhanced AKT-PAK axis can robustly reverse energy crises, protect neuron survival, and facilitate CNS regeneration, thus providing a more promising therapeutic strategy for brain injury and ischemia. Accomplishment 4. Oligodendrocytes enhance axonal energy metabolism by deacetylation of mitochondrial proteins through transcellular delivery of SIRT2 (Chamberlain and Huang et al., Neuron (in press)) Neurons require mechanisms maintaining local ATP supply in distal axons and synapses, which are particularly vulnerable to bioenergetic failure clinically relevant to axonal pathology and disease progression in neurodegenerative diseases. Thus, revealing mechanisms maintaining axonal energy supply is an emerging frontier for therapeutic investigation. Considering intricate networks in the human brain where billions of neurons and glial cells wire together, a comprehensive maintenance of axonal bioenergetic status must include the contribution of glial cells. Oligodendrocytes (OLs) serve as myelinating cells surrounding axons of the CNS; this unique structure ideally positions OLs to support axonal energy metabolism. It is critical to investigate OL-axon cross talk in the active maintainance or boosting of axonal mitochondrial bioenergetics. Our recent study reveals a new transcellular signaling pathway through which OL-derived NAD-dependent deacetylase sirtuin 2 (SIRT2) boosts axonal energy metabolism by deacetylation of mitochondrial proteins ANT1/ANT2. SIRT2 is undetectable in neurons but highly enriched in mature OLs and released within exosomes. Knockdown of SIRT2 in OLs or deletion of sirt2 gene in mice abolishes the OL-axon cross talk in boosting axonal energetics. Injection of OL-derived exosomes rescues axonal mitochondrial deficiency in the spinal cord of sirt2 KO mice. This study suggests that exosome-mediated OL-to-axon delivery of SIRT2 is an efficient and robust mechanism for boosting axonal mitochondrial energetic capacity, thus providing a therapeutic target for restoring axonal energy metabolism in neurological disorders.