Mitochondrial biogenesis for the treatment of spinal cord injury

Abbreviations

5-HTR

5-hydroxytryptamine receptor

7,8-DHF

dihydroxyflavone

Ac

acetyl group

AICAR

5-aminoimidazole-4-carboxamide ribonucleotide

Akt

protein kinase B

AMPK

adenosine monophosphate-activated kinase

AP-1

activating protein 1

ATP

adenosine triphosphate

BSCB

blood–spinal cord barrier

cGMP

cyclic guanosine monophosphate

CNS

central nervous system

CO

carbon monoxide

cyt c

cytochrome c

DEX

dexmedetomidine

DRP1

dynamin-related protein 1

EAAT

excitatory amino acid transporter

eNOS

endothelial nitric oxide synthase

ETC

electron transport chain

FDA

Food and Drug Administration

FIS1

fission 1

Glu-R

glutamate receptor

GPCR

G protein-coupled receptor

HO-1

heme oxygenase 1

IL-6

interleukin 6

MAPK

mitogen-activated protein kinase

MB

mitochondrial biogenesis

Mdivi-1

mitochondrial division inhibitor 1

Mfn

mitofusin

Mn

manganese

mPTP

mitochondrial permeability transition pore

mtDNA

mitochondrial DNA

Nrf

nuclear respiratory factor

NSC

neuronal stem cell

OPA1

optic atrophy 1

OXPHOS

oxidative phosphorylation

P

phosphate group

PDE

phosphodiesterase

PGC-1α

peroxisome proliferator-activated receptor-gamma coactivator 1 alpha

PI3K

phosphoinositide-3 kinase

PINK1

PTEN-induced kinase 1

PPAR

peroxisome proliferator-activated receptor

ROS

reactive oxygen species

SCI

spinal cord injury

SIRT1

sirtuin-1

TFAM

mitochondrial transcription factor A

TMP

tetramethylpyrazine

TNFα

tumor necrosis factor alpha

TZDs

thiazolidinediones

U

ubiquitin group

β-AR

β-adrenergic receptor

Introduction

Neuronal integrity is dependent on mitochondrial homeostasis and function, resulting in the central nervous system (CNS) being particularly sensitive to mitochondrial dysfunction ( ). Spinal cord injury (SCI) results in an intricate pathology involving heterogeneous cell types with unique roles in injury and recovery. Following SCI, mitochondria are dysfunctional, resulting in an array of consequences including decreased mitochondrial respiration and adenosine triphosphate (ATP) production, depolarization of the mitochondrial membrane, mitochondrial DNA (mtDNA) fragmentation, oxidative stress, compromised calcium homeostasis, altered mitochondrial dynamics, and cell death ( ). These cellular dysfunctions contribute to the secondary injury cascade of SCI, exacerbating injury, and hindering recovery.

Mitochondrial biogenesis (MB) is an intricate process involving the generation of new, functional mitochondria ( ). In recent years, there has been an increase in published data documenting that pharmacological induction of MB restores mitochondrial and organ function following various pathological events in vivo, including SCI ( ). These findings, in conjunction with the plethora of evidence indicating that restoring mitochondrial homeostasis promotes recovery following SCI, speak to the potential for this treatment strategy. Additionally, in vitro reports have elucidated cell type-specific consequences of mitochondrial dysfunction and MB in SCI-relevant cell types, which could aid in the future development of targeted therapies.

Importantly, there exists an increasing number of U.S. Food and Drug Administration (FDA)-approved pharmaceuticals capable of MB induction, demonstrating the clinical applicability of this approach ( ). This perspective will briefly review and explore CNS cell type-specific mitochondrial dysfunction and MB, as well as describe current therapeutic strategies employing inducers of MB post-SCI.

Mitochondrial dysfunction

Mitochondrial dysfunction results from alterations to homeostatic mitochondrial processes, leading to deficient energy metabolism, primarily through decreased oxidative phosphorylation (OXPHOS) and ATP synthesis. Examples of such alterations include inadequate mitochondrial number and/or mass, altered membrane potential, mitochondrial DNA (mtDNA) mutation/fragmentation, defective electron transport chain (ETC) activity, increased production of reactive oxygen species (ROS), intracellular calcium dysregulation, and impaired mitochondrial dynamics and mitophagy ( ; ).

Due to high energy demand within the CNS, mitochondrial dysfunction and ensuing loss of ATP can prevent the function of various ATPases (H ⁺ , Ca ^{2 +} , Na ⁺ /K ⁺ -ATPase) required for effective neurotransmission, thereby deregulating cellular ion gradients. Mitochondrial dysfunction can also disrupt calcium buffering and signaling, which is crucial for neuronal synapses, leading to calcium overload and excitotoxicity ( ). In SCI pathology, activated astrocytes and glial cells release pro-inflammatory cytokines, resulting in mitochondrial dysfunction and ultimately apoptosis ( ). Additionally, SCI is characterized by vasculature disruption, leading to loss of blood flow and local ischemia, which contributes to oxidative stress, mitochondrial dysfunction and the propagation of cell death observed during secondary injury ( Fig. 1 ) ( ). Therefore, evidence suggests that restoring mitochondrial function could be an effective strategy to mediate multiple facets of injury progression and aid in preventing further cell death.

Mitochondrial biogenesis

Although many studies exist assessing mitochondria-targeted strategies for treatment of SCI, the majority address singular aspects of downstream mitochondrial dysfunction, such as increasing antioxidant defenses or inhibiting opening of the mitochondrial permeability transition pore (mPTP) ( ). In contrast, MB is the production of new, functional mitochondria via the growth and division of pre-existing mitochondria, which could therefore address multiple, if not all, facets of mitochondrial dysfunction ( Fig. 2 ). This complex process involves the cooperation of multiple cellular pathways, requiring the synthesis of mtDNA, transcription and translation of mitochondrial- and nuclear-encoded proteins and ultimately assembly of ETC complexes ( ).

Regulation of MB

Coordination of the nuclear and mitochondrial genomes is modulated by transcriptional coactivators, with the most relevant to MB being the “master regulator” peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1α) ( ). Activation of PGC-1α can be initiated via multiple post-translational modifications, including deacetylation by sirtuin-1 (SIRT1) and phosphorylation by adenosine monophosphate-activated kinase (AMPK) and p38-mitogen-activated protein kinase (MAPK) ( ). Additionally, agonism of G-protein-coupled receptors (GPCRs), such as 5-hydroxytryptamine (5-HTRs) and β-adrenergic receptors (β-ARs), can activate the protein kinase B (Akt)/endothelial nitric oxide synthase (eNOS)/cyclic guanosine monophosphate (cGMP) pathway leading to activation of PGC-1α, translocation to the nucleus and, subsequently, induction of MB ( Fig. 3 ) ( ; ; ). Importantly, studies have shown that PGC-1α is decreased in the spinal cord after SCI, indicative of disrupted MB ( ; ).

PGC-1α regulates MB through interactions with transcription factors such as peroxisome proliferator-activated receptors (PPARs) and nuclear respiratory factors (Nrf1/2), among others ( ; ). PPARs are involved in the expression of fatty acid oxidation and Krebs cycle enzymes and OXPHOS components ( ; ). Activation of Nrf1/2 induces transcription of mitochondrial transcription factor A (TFAM) ( ), which translocates to the mitochondria, where it activates mitochondrial gene expression and mtDNA replication ( ). Coordination of these transcription factors via PGC-1α culminates in the induction of MB.

Intimately related to MB is mitochondrial dynamics, namely fusion and fission. Fusion is the joining of two mitochondria mediated by mitofusins (Mfn1/2) and optic atrophy 1 (OPA1), whereas fission initiates cleavage and division of mitochondria, and is mediated, in part, by dynamin-related protein 1 (DRP1) and outer membrane receptor fission 1 (FIS1). Dysfunctional mitochondria contain impaired proteins, damaged membranes and fragmented mtDNA, increasing fission mechanisms and mitophagy, which is the selective degradation of damaged mitochondria by autophagosomes mediated, in part, by PTEN-induced kinase 1 (PINK1) and E3-ubiquitin ligase (Parkin) interaction ( Fig. 4 ) ( ). Conversely, promotion of fusion mechanisms has been implicated in MB and recovery ( ). Proper balance of MB, dynamics and mitophagy is critical for mitochondrial function and response to various stressors, including SCI.

Cell type-specific mitochondrial dysfunction and MB

SCI is a complex pathology involving heterogeneous cell types with distinct roles in the progression of injury and recovery. Many in vivo studies exist evaluating the global effects of mitochondrial-based therapies for SCI, while few reports exist detailing cell type-specific effects. Understanding the role of mitochondrial dysfunction and MB in relevant cell types can uncover not only underexplored mechanisms, but also potential therapeutic strategies following SCI.

Neurons

In addition to their primary role in bioenergetics, neuronal mitochondria contribute to regulation of synaptic transmission, calcium homeostasis, neuronal excitability and response to stress ( ). Neurons are dependent on efficient ATP regulation and have limited capacity to buffer oxidative stress. As such, neurons are particularly vulnerable to mitochondrial dysfunction, resulting in excitotoxicity, calcium overload, axon demyelination and cell death ( ).

In the presence of mitochondrial dysfunction in vitro, MB compounds can improve mitochondrial homeostasis and neuronal survival. For example, mitochondrial division inhibitor-1 (Mdivi-1), a DRP1 inhibitor and inducer of MB, improved mitochondrial function and neural conductance in cultured spinal cord neurons following glutamate-induced ischemia-reperfusion. Treatment also reduced oxidative stress markers, neuronal injury and apoptosis in this model ( ). Serotonin, a neurotransmitter implicated in mitochondrial and functional recovery from SCI, enhanced mtDNA content, mitochondrial concentration and mitochondrial function, while demonstrating neuroprotective effects against oxidative stress in cultured rodent cortical neurons ( ).

MB is also implicated in stem cell differentiation and neural fate commitment. Treatment with bezafibrate, a PPAR agonist, evoked up-regulation of MB-related genes and improved cell viability, mitochondrial membrane potential and cell number during late-stage differentiation in human-induced pluripotent stem cells ( ). Furthermore, inherent increases in mtDNA content and MB-related gene and protein expression exist during differentiation of human neuronal stem cells (NSCs) into motor neurons ( ). NSC transplantation is being developed to promote recovery of the neural network after SCI ( ); the reliance of motor neuron differentiation on MB, however, suggests that differentiating NSCs may be vulnerable to mitochondrial dysfunction after injury ( ). Therefore, concurrent treatment employing NSCs and MB compounds may enhance successful motor neuron differentiation, thereby improving NSC-induced neurogenesis and recovery post-SCI.

Astrocytes

Integral within the CNS, astrocytes maintain neuronal energy, metabolism and structural support, modulation of synaptic transmission, regulation of intercellular ion concentration, vasomodulation and promotion of the myelinating activity of oligodendrocytes. Following SCI, astrocytes undergo complex morphological, gene expression and functional changes ( ). Given that defects in astrocyte activity and metabolism are associated with a variety of neuropathological disorders ( ), maintaining the metabolic activity of astrocytes is likely crucial for neuronal function post-SCI.

Aβ1–42, a toxic peptide aggregate found in Alzheimer’s disease pathology, increases MB in astrocytes, while inducing lipid peroxidation, apoptosis and cell death in neurons. Despite these deleterious neuronal effects, increased neuronal survival, restored mitochondrial homeostasis, improved resistance to oxidative damage and modulation of the neuroinflammatory response were documented when neurons and astrocytes were co-cultured ( ). The neuroprotective nature of astrocytic MB reported in this study is compelling, revealing a potential therapeutic target following SCI.

Manganese (Mn) targets astrocytes and promotes the expression of pro-inflammatory cytokine interleukin-6 (IL-6) and tumor necrosis factor alpha (TNFα), leading to mitochondrial dysfunction and neurotoxicity in vitro. In mouse cerebral astrocytes, Mn-induced inflammation led to decreased mitochondrial mass, excessive fission, as well as impaired basal and ATP-linked mitochondrial respiration ( ). Interestingly, the antioxidant mito-apocynin attenuated this inflammatory response and restored mitochondrial mass ( ). While Mn toxicity is often observed following occupational or environmental exposure ( ), this impaired astrocytic mitochondrial profile presents similarly to that following SCI ( ). As such, future studies should investigate the therapeutic potential of mito-apocynin in mediating astrocytic dysfunction following SCI.

In addition to pharmacological induction, internally driven MB can occur as a programmed response to aid in the recovery of astrocytes following oxidative insults ( Fig. 5 ) ( ; ). Oxidant injuries stimulate the expression of heme oxygenase-1 (HO-1) in astrocytes. Carbon monoxide (CO), a by-product of HO-1-driven heme degradation, regulates energy metabolism and can mitigate tissue injury and inflammation in neurological diseases. In addition, HO-1-derived CO increases MB, as evidenced by increased PGC-1α and ATP synthesis in astrocytes ( ). Therefore, astrocytic HO-1 induction during ischemic events may be endogenously protective via stimulation of MB, thereby hindering propagation of ischemic damage. Furthermore, reports demonstrate that endogenous and exogenous CO can promote MB in cerebral astrocytes in vitro ( ). As such, CO-mediated MB in astrocytes may be protective following SCI.

Tags: Diagnosis and Treatment of Spinal Cord Injury

Nov 9, 2024 | Posted by drzezo in NEUROLOGY | Comments Off

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