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

National Institute Of Neurological Disorders And Stroke

Investigators

Linked publications, trials & patents

Abstract

Accomplishment 1. Revealing an energy signaling pathway that captures presynaptic mitochondria to sustain synaptic efficacy (Li et al., Nature Metabolism 2020; Li and Sheng, Nature Reviews Neuroscience 2022) Presynaptic mitochondria are essential for sustaining effective neurotransmission by generating ATP locally and buffering presynaptic Ca2+ effectively. However, only ~33-50% of presynaptic terminals contain mitochondria, highlighting the importance of mechanisms that recruit and retain them. We discovered that sustained synaptic activity induces presynaptic energy decline, which is restored by an AMPK-PAK energy signaling pathway that drives recruitment of axonal mitochondria. Specifically, activity-driven energy deficits activate AMPK-PAK signaling, leading to myosin VI (myo6) phosphorylation. This promotes the capture of motile mitochondria at presynaptic terminals through coordinated interactions between Myo6 and SNPH. Mitochondria anchored on presynaptic F-actin via SNPH ensures local supply of ATP during periods of high demand, thereby sustaining prolonged synaptic transmission. Disrupting this signaling crosstalk results in synaptoenergetic deficits, impairing synaptic efficacy and reducing recovery from synaptic depression. Thus, our study establishes an energy-sensitive mechanism capturing presynaptic mitochondria, which maintains synaptic efficacy and fine-tunes synaptic plasticity. Accomplishment 2. Promoting CNS regeneration after spinal cord injury (SCI) by enhancing axonal mitochondrial transport (Han et al., Cell Metabolism 2020; Cheng et al., Neuron 2022) Mature CNS neurons typically fail to regenerate after injury, in part because regeneration is a highly energy demanding. In SCI, acute mitochondrial damage exacerbates this problem by creating a local energy crisis in long-projecting corticospinal tract (CST) axons. We hypothesized that injury-induced mitochondrial damage imposes a bioenergetic restriction that underlies regeneration failure. To test this, we collaborated with Dr. Xiao-Ming Xu's lab (Indiana University) using three SCI models in Snph KO mice, in which axonal mitochondrial transport is robustly increased. We found that Snph KO mice exhibit: (1) enhanced CST axon regeneration across the lesion, (2) accelerated regrowth of monoaminergic axons across a transection gap, and (3) increased compensatory sprouting of uninjured CST axons. These effects arise from enhanced delivery of healthy mitochondria from the motor cortex into regenerating CST axons, thereby restoring local energy supply to support axonal survival and regeneration. Thus, our work establishes that restoring energy supply by enhancing mitochondrial transport into injured axons is a promising strategy to promote axonal regeneration in the CNS. Accomplishment 3. Reprogramming an AKT-PAK5 signaling axis to remobilize damaged mitochondria for replacement, facilitating neuronal survival and regeneration after injury-ischemia (Huang et al., Current Biology 2021; Huang and Sheng, Cell Regeneration 2022) Mitochondrial dysfunction and energy failure are hallmarks of ischemic injury, often leading to neuronal death. In mature CNS neurons, axonal mitochondrial integrity and content decline after oxygen and glucose deprivation, causing severe ATP deficits and axonal degeneration. High SNPH expression in adult neurons keeps most axonal mitochondria stationary, further limiting the ability to respond to injury. These intrinsic and extrinsic constraints create an acute energy crisis in injured axons. We identified a novel bioenergetic repair signaling axis that restores axonal energy supply by reprogramming mitochondrial trafficking in response to injury-ischemic stress. PAK5, a brain mitochondria-associated kinase whose expression declines with neuronal maturation, is spatiotemporally activated in axons following ischemic injury. Activation of PAK5 signaling remobilizes damaged mitochondria by inactivating the axonal mitochondrial anchor SNPH, facilitating their replacement with healthy mitochondria. Injury-ischemia-induced AKT signaling further activates PAK5, enhancing local ATP supply and supporting neuronal survival and regeneration. Thus, this study defines a mitochondria-targeted PAK5 signaling that senses and responds to energy deficits, providing a potential therapeutic strategy to reverse axonal energy crisis and promote neuronal survival after ischemic injury. Accomplishment 4. Identifying an oligodendrocyte-to-axon transcellular signaling pathway required for maintaining axonal bioenergetic metabolism (Chamberlain and Huang et al., Neuron 2021; Li and Sheng, Current Opinion of Neuroscience 2023) Neurons rely on mechanisms that maintain local ATP supply in distal axons and synapses, regions particularly vulnerable to bioenergetic failure, which contributes to axonal pathology in neurodegenerative diseases. Understanding how axonal energy supply is maintained is therefore an important therapeutic frontier. In the complex networks of the CNS, where billions of neurons and glial cells wire together, glial cells play a critical role in sustaining axonal bioenergetics. Oligodendrocytes (OLs) serve as myelinating cells surrounding axons of the CNS; this unique structure ideally positions OLs to support axonal energy metabolism. We discovered a transcellular signaling pathway in which OLs support axonal energy metabolism via exosome-mediated delivery of SIRT2, an NAD-dependent deacetylase. SIRT2, highly enriched in mature OLs but undetectable in neurons, deacetylates mitochondrial proteins ANT1/ANT2 to enhance axonal ATP production. Knockdown of SIRT2 in OLs or deletion of the Sirt2 gene in mice abolishes this OL–axon crosstalk. Remarkably, injection of OL-derived exosomes rescues axonal mitochondrial deficits in the spinal cord of Sirt2 KO mice. This study demonstrates that exosome-mediated OL-to-axon transfer of SIRT2 is a robust mechanism for boosting axonal mitochondrial energetic capacity, providing a promising therapeutic target to restore axonal energy deficits in neurological disorders. Accomplishment 5. Restoring synaptoenergetics alleviates mood and synaptic fluctuations in bipolar disorder (Li, Xiong et al., revision submitted to Nature Metabolism) Synaptic activity demands high ATP consumption, making presynaptic terminals particularly vulnerable to disruptions in presynaptic bioenergetics—a process termed “synaptoenergetics”. In bipolar disorder (BD), manic episodes are characterized by elevated mood, arousal, and psychological energy, suggesting synaptic instability. To explore the cellular basis, we developed two BD neuronal models: human iPSC-derived cortical neurons from BD patients and mouse neurons with reduced expression of AKAP11, a BD-risk gene. Both models exhibit impaired presynaptic mitochondrial retention, leading to accelerated energy depletion during synaptic activity and increased variability in synaptic strength. Notably, human BD neurons show reduced expression of syntaphilin (SNPH), the axonal mitochondrial anchor required to capture mitochondria at presynaptic terminals. Consistently, Snph knockout mice display mania-like behaviors, which are reversed by lithium, a first-line mood-stabilizer. Lithium restores presynaptic ATP supply, reduces synaptic variability, and enhances synaptic recovery in BD and Snph knockout neurons. Mechanistically, lithium promotes mitochondrial Ca2+ efflux via the Na+/Ca2+/Li+ exchanger, sustaining Miro1-Ca2+ signaling on the mitochondrial surface and prolonging mitochondrial retention at presynaptic sites. These findings establish synaptoenergetic failure as a key cellular mechanism underlying BD-associated synaptic and mood instability and provide a framework for developing therapeutic strategies that restore presynaptic bioenergetics.