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

National Institute Of Neurological Disorders And Stroke

Investigators

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Abstract

Accomplishment 1. Reveal an energy signaling pathway that recruits and captures presynaptic mitochondria to sustain synaptic efficacy (Li et al., Nature Metabolism 2020; Li and Sheng, Nature Reviews Neuroscience 2022) Presynaptic mitochondria play an essential role in maintaining effective synaptic transmission by generating ATP and sequestering presynaptic Ca2+. Given that only 33% of presynaptic terminals retain mitochondria, revealing mechanisms for recruiting and retaining presynaptic mitochondria will advance our knowledge as how neurons sustain synaptic efficacy and plasticity. In this study, we reveal that sustained activity induces presynaptic energy deficits that can be effectively recovered by recruiting mitochondria through an AMPK-PAK energy signaling pathway. Motile 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 where mitochondria are anchored on F-actin via SNPH. This pathway maintains presynaptic ATP supply during intensive synaptic activity. Disrupting this signaling crosstalk triggers synaptoenergetic deficits, leading to impaired synaptic efficacy and reduced recovery from synaptic depression after prolonged synaptic activity. Thus, our study reveals an energy-sensitive capture of presynaptic mitochondria, thus fine-tuning synaptic plasticity and maintaining synaptic efficacy. Accomplishment 2. Promoting CNS regeneration after spinal cord injury (SCI) by deleting mitochondrial anchor SNPH (Han et al., Cell Metabolism 2020; Cheng et al., Neuron 2022) Mature CNS neurons typically fail to regrowth after injury, and regeneration requires a high level of energy consumption. This is particularly problematic in SCI that acutely 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 energetic restriction that accounts for regeneration failure. To test this, we collaborated with Dr. Xiao-Ming Xu's lab (Indiana University) by using three SCI models in Snph KO mice, in which axonal mitochondrial transport is robustly increased. We demonstrate that Snph KO 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. 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 CNS axonal regeneration after injuries. Accomplishment 3. Reprogramming an energetic AKT-PAK5 signaling axis remobilizes damaged mitochondria for replacement and thus facilitates neuron survival and regeneration after injury-ischemia (Huang et al., Current Biology 2021; Huang and Sheng, Cell Regeneration 2022) Mitochondrial dysfunction and energy crisis are the hallmarks of ischemic injury that typically leads to the cell death within affected brain region. In mature CNS neurons, axonal mitochondrial integrity and content are reduced and ATP levels are significantly declined after oxygen and glucose deprivation, contributing to axonal degeneration. In adult brains, highly enriched SNPH expression results in the vast majority of axonal mitochondria remaining stationary after damaged. These extrinsic insults and intrinsic restrictions lead to an acute energy crisis in injured axons. In this study, we reveal a novel 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 when neurons mature. PAK5 synthesis and signaling is spatiotemporally reactivated locally 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 further activates PAK5 and thus boosts local energy supply by recruiting healthy mitochondria. Thus, our study in in vitro and in vivo models reveals a new mitochondrial signaling axis that responds to injury and ischemia and provides a potential therapeutic strategy for neuronal survival and regeneration by reversing energy crisis. Accomplishment 4. Oligodendrocytes enhance axonal energy metabolism by deacetylation of mitochondrial proteins through transcellular delivery of SIRT2 (Chamberlain and Huang et al., Neuron 2021; Li and Sheng, Current Opinion of Neuroscience 2023) 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 or boosting 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 bioenergetics 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. In this study, we reveal 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 bioenergetics. 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 deficits in neurological disorders.