I am a scientist specialized in mitochondria and genetics, but above all, I am just curious guy who loves learning new things.
It's not the economy, it's the energy, stupid!
The mito-what? Mitochondria produce most of the energy of our cells and recent studies show that the dysfunction of these cellular power plants may be important for the development of multiple sclerosis (MS). Better yet, protecting mitochondria may be the key to stopping MS.
Why are mitochondria important for neurons? Neuronal cells need a lot of energy, produced mainly by mitochondria. Also, they communicate using electrically charged molecules (ions) and mitochondria are an important player in regulating those molecules. Finally, mitochondria in bad shape produce a lot of oxidative stress which can harm neurons.
And I am guessing that in MS mitochondria are not in very good shape? Exactly, although researchers did not know if this was a consequence of MS, or a cause. But recent evidence shows that mitochondrial dysfunction is an important step in the development of MS.
How’s that? MS is caused by an autoimmune response, where the immune system attacks neuronal cells as if they were external invaders. This attack causes inflammation and loss of myelin, the substance that protects neurons, like plastic around electric cables. Without this isolating layer there is a loss of conduction (energy is lost), so more energy is needed. The neuron then increases mitochondrial activity to increase energy production, but it comes with a price.
What do you mean? Like in an actual power plant, increasing production also means increasing pollution, in this case oxidative stress, which will further attack the cell, including mitochondria itself. Eventually, mitochondria breaks under the attacks and energy production drops, causing neuronal dysfunction.
So protecting mitochondria from itself may prevent MS? That’s right! By protecting mitochondria against mitochondrial oxidative stress energy production would be spared, slowing, or even stoping, the progression of MS.
Abstract: Multiple sclerosis (MS) is a neuro-inflammatory and demyelinating disease. Downregulation of neuronal mitochondrial gene expression and activity have been reported in several studies of MS. We have previously shown that hemoglobin-β (Hbb) signals to the nucleus of neurons and upregulates H3K4me3, a histone mark involved in regulating cellular metabolism and differentiation. The present study was undertaken to evaluate the effect of erythropoietin (EPO) on the upregulation of hemoglobin and mitochondrial-associated neuroprotection. We found that administering EPO (5000 IU/kg intraperitoneally) to mice upregulated brain Hbb expression, levels of H3K4me3, expression of mitochondrial complex III, complex V, and mitochondrial respiration. We also found that the neuronal mitochondrial metabolite N-acetylaspartate (NAA), a marker of neuronal mitochondrial activity, was increased with EPO treatment. Further, we measured the effects of EPO on preventing mitochondrial deficits in the cuprizone toxic demyelinating mouse model of MS. We found that EPO prevented cuprizone-mediated decreases in Hbb, complex III, and NAA. Our data suggest that EPO mediated regulation of Hbb supports neuronal energetics and may provide neuroprotection in MS and other neurodegenerative diseases where a dysfunction of mitochondria contributes to disease.
Pub.: 01 Mar '18, Pinned: 09 Mar '18
Abstract: Multiple sclerosis (MS) is characterized by demyelination and progressive neurological disability. Previous studies have reported defects to mitochondria in MS including decreased expression of nuclear encoded electron transport chain subunit genes and inhibition of respiratory complexes. We previously reported increased levels of the hemoglobin β subunit (Hbb) in mitochondrial fractions isolated from postmortem MS cortex compared to controls. In the present study, we performed immunohistochemistry to determine the distribution of Hbb in postmortem MS cortex and identified proteins which interact with Hbb by liquid chromatography tandem mass spectrometry (LC-MS/MS). We found that Hbb was enriched in pyramidal neurons in internal layers of the cortex and interacts with subunits of ATP synthase, histones, and a histone lysine demethylase. We also found that Hbb is present in the nucleus and that expression of Hbb in SH-SY5Y neuroblastoma cells increased trimethylation of histone H3 on lysine 4 (H3K4me3), a histone mark that regulates cellular metabolism. These data suggest that Hbb may be a part of a mechanism linking neuronal energetics with epigenetic changes to histones in the nucleus and may provide neuroprotection in MS by supporting neuronal metabolism.
Pub.: 27 Jan '16, Pinned: 09 Mar '18
Abstract: The induction of mitochondrial biogenesis could potentially alleviate mitochondrial and muscle disease. We show here that dimethyl fumarate (DMF) dose-dependently induces mitochondrial biogenesis and function dosed to cells in in vitro, and also dosed in vivo to mice and humans. The induction of mitochondrial gene expression is more dependent on its target Nrf2 than hydroxycarboxylic acid receptor 2 (HCAR2). Thus, DMF induces mitochondrial biogenesis primarily through its action on Nrf2, and is the first drug demonstrated to increase mitochondrial biogenesis with in vivo human dosing. The observation that DMF stimulates mitochondrial biogenesis, gene expression and function suggests that it could be considered for mitochondrial disease therapy and/or therapy in muscle disease in which mitochondrial function is important.
Pub.: 02 May '17, Pinned: 06 Mar '18
Abstract: We used the Plp1-overexpressing transgenic mouse model to investigate whether progressive demyelination of axons results in adaptive changes involving mitochondria within the axons. These models have myelinated axons from birth but gradually lose myelin and develop axonal loss associated with progressive neurological disability analogous to patients with secondary progressive mulltiple sclerosis (SPMS). At 1 and 2 months, electron microscopy demonstrated a significant increase in intraaxonal mitochondrial density in the homozygous line 72 Plp1-overexpressing mice compared with wild type (1.43 +/- 0.31 vs. 0.84 +/- 0.16 microm(-3), P = 0.031; 1.66 +/- 0.11 vs. 0.92 +/- 0.43 microm(-3), P = 0.02) and a significant increase at 1 and 4 months in the density of mitochondria in the surrounding cells in the same mice (1.86 +/- 0.31 vs. 0.81 +/- 0.30 microm(-3), P = 0.006; 2.77 +/- 0.44 vs. 1.37 +/- 0.42 microm(-3), P = 0.016). At both 1 and 4 months, COX histochemistry and time-lapse histochemistry demonstrated a significant increase in mitochondrial activity and rate of mitochondrial activity in the homozygous Plp1-overexpressing mouse optic nerve compared with the wild type (112.37 +/- 11.9 vs. 136.89 +/- 9.1 MeanD, P = 0.006; 128.02 +/- 3.0 vs. 188.77 +/- 9.7 MeanD P < 0.001; Rate -0.78 +/- 0.25 vs. -0.58 +/- 0.15 MeanD min(-1), P < 0.001; -1.48 +/- 0.15 vs. 0.51 +/- 0.17 MeanD min(-1), P < 0.001, respectively). We propose that adaptive changes involving mitochondria occur within CNS axons in Plp1-overexpressing mice, which may be detrimental to long-term viability. Analogous changes occurring in chronically demyelinated axons in MS lesions would be one mechanism increasing axonal vulnerability in SPMS.
Pub.: 23 Sep '08, Pinned: 06 Mar '18
Abstract: Axonal pathology in multiple sclerosis (MS) has been described for over a century, but new insights into axonal loss and disability have refocused interest in this area. There is evidence of oxidative damage to mitochondrial DNA in chronic MS plaques, suggesting that mitochondrial failure may play a role in MS pathology. We propose that in the chronic absence of myelin the maintenance of conduction relies partially on an increase in mitochondria to provide energy. This increased energy requirement also promotes reactive oxygen species (ROS), because most intraaxonal ROS are generated by mitochondria. If antioxidant defenses are overwhelmed by an excess of ROS, this may result in damage to the axon. Our aim was to investigate whether a chronic lack of myelin results in adaptive changes involving mitochondria within the axon. We investigated this in the shiverer mouse. This myelin basic protein gene mutant provides a model of how adult central nervous system (CNS) axons cope with the chronic absence of a compact myelin sheath. Cytochrome c histochemistry demonstrated a twofold increase in mitochondrial activity in white matter tracts of shiverer, and electron microscopy confirmed a significantly higher number of mitochondria within the dysmyelinated axons. Our data demonstrate that there are adaptive changes involving mitochondria occurring within CNS axons in shiverer mice in response to a lack of myelin. This work contributes to our understanding of the adaptive changes occurring in response to a lack of myelin in a noninflammatory environment similar to the situation seen in chronically demyelinated MS plaques.
Pub.: 24 Mar '06, Pinned: 06 Mar '18
Abstract: Recent studies report that loss and dysfunction of mitochondria and peroxisomes contribute to the myelin and axonal damage in multiple sclerosis (MS). In this study, we investigated the efficacy of lovastatin and AMPK activator (AICAR) combination on the loss and dysfunction of mitochondria and peroxisomes and myelin and axonal damage in the spinal cords, relative to the clinical disease symptoms, using a mouse model of experimental autoimmune encephalomyelitis (EAE, a model for MS). We observed that lovastatin and AICAR treatments individually provided partial protection of mitochondria/peroxisomes, myelin/axons, and thus partial attenuation of clinical disease in EAE mice. However, treatment of EAE mice with lovastatin and AICAR combination provided greater protection of mitochondria/peroxisomes and myelin/axons, and greater improvement in clinical disease as compared to individual drug treatments. In spinal cords of EAE mice, lovastatin-mediated inhibition of RhoA and AICAR-mediated activation of AMPK cooperatively enhanced expressions of transcription factors and regulators (e.g. PPARα/β, SIRT-1, NRF-1, and TFAM) required for biogenesis and functions of mitochondria (e.g. OXPHOS, MnSOD) and peroxisomes (e.g. PMP70 and catalase). In summary, these studies document that oral medication of combination of lovastatin and AICAR, which are individually known to have immunomodulatory effects, provides potent protection and repair of inflammation-induced loss and dysfunction of mitochondria and peroxisomes as well as myelin and axonal abnormalities in EAE. Since statins are known to provide protection in progressive MS (Phase II study), these studies support that supplementation of AMPK activator to statin treatment may provide greater efficacy against MS disease. This article is protected by copyright. All rights reserved.
Pub.: 14 Jan '18, Pinned: 06 Mar '18
Abstract: Brain injuries in multiple sclerosis (MS) involve immunopathological, structural and metabolic defects on myelin sheath, oligodendrocytes (OLs), axons and neurons suggesting that different cellular mechanisms ultimately result in the formation of MS plaques, demyelination, inflammation and brain damage. Bioenergetics, oxygen and ion metabolism dominate the metabolic and biochemical pathways that maintain neuronal viability and impulse transmission which directly or indirectly point to mitochondrial integrity and adenosine triphosphate (ATP) availability indicating the involvement of mitochondria in the pathogenesis of MS. Loss of myelin proteins including myelin basic protein (MBP), proteolipid protein (PLP), myelin associated glycoprotein (MAG), myelin oligodendrocyte glycoproetin (MOG), 2, 3,-cyclic nucleotide phosphodiestarase (CNPase); microglia and microphage activation, oligodendrocyte apoptosis as well as expression of inducible nitric oxide synthase (i-NOS) and myeloperoxidase activities have been implicated in a subset of Balo's type and relapsing remitting MS (RRMS) lesions indicating the involvement of metabolic defects and oxidative stress in MS. Here, we provide an insighting review of defects in cellular metabolism including energy, oxygen and metal metabolism in MS as well as the relevance of animal models of MS in understanding the molecular, biochemical and cellular mechanisms of MS pathogenesis. Additionally, we also discussed the potential for mitochondrial targets and antioxidant protection for therapeutic benefits in MS.
Pub.: 17 Dec '17, Pinned: 06 Mar '18
Abstract: The sigma-1 receptor (Sig-1R) is a chaperone that resides mainly at the mitochondrion-associated endoplasmic reticulum (ER) membrane (called the MAMs) and acts as a dynamic pluripotent modulator in living systems. At the MAM, the Sig-1R is known to play a role in regulating the Ca(2+) signaling between ER and mitochondria and in maintaining the structural integrity of the MAM. The MAM serves as bridges between ER and mitochondria regulating multiple functions such as Ca(2+) transfer, energy exchange, lipid synthesis and transports, and protein folding that are pivotal to cell survival and defense. Recently, emerging evidences indicate that the MAM is critical in maintaining neuronal homeostasis. Thus, given the specific localization of the Sig-1R at the MAM, we highlight and propose that the direct or indirect regulations of the Sig-1R on mitochondrial functions may relate to neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS). In addition, the promising use of Sig-1R ligands to rescue mitochondrial dysfunction-induced neurodegeneration is addressed.
Pub.: 18 Sep '17, Pinned: 06 Mar '18
Abstract: Mitochondrial dysfunction is associated with neuroinflammation and neurodegeneration disease, but its role as a driver in these processes is uncertain. Understanding the pathogenesis of inherited mitochondrial disorders may help us to uncover mechanisms involved during acquired mitochondrial dysfunction. We review the mechanisms of mitochondrial dysfunction in Leber's hereditary optic neuropathy and multiple sclerosis and discuss shared clinical and molecular features in both conditions. Targeting mitochondrial pathways involved in inflammation or apoptosis may be a possible therapeutic approach in multiple sclerosis.
Pub.: 03 Jul '17, Pinned: 06 Mar '18
Abstract: Multiple sclerosis (MS) is one of the most widespread chronic neurological diseases that manifests itself by progressive demyelination in the central nervous system. The study of MS pathogenesis begins with the onset of the relapsing-remitting phase of the disease, which becomes apparent due to microglia activation, neuroinflammation and demyelination/remyelination in the white matter. The following progressive phase is accompanied by severe neurological symptoms when demyelination and neurodegeneration are spread to both gray and white matter. In this review, we discuss a possible role of mitochondrial reactive oxygen species (mtROS) in MS pathogenesis, mechanisms of mtROS generation and effects of some mitochondria-targeted antioxidants as potential components of MS therapy.In the early phase of MS, mtROS stimulate NLRP3 inflammasomes, which is critical for the formation of local inflammatory lesions. Later, mtROS contribute to blood-brain barrier disruption induced by mediators of inflammation, followed by infiltration of leukocytes. ROS generated by leukocytes and activated microglia promote mitochondrial dysfunction and oligodendrocyte cell death. In the progressive phase, neurodegeneration also depends on excessive mtROS generation. Currently, only a few immunomodulatory drugs are approved for treatment of MS. These drugs mainly reduce the number of relapses but do not stop MS progression. Certain dietary and synthetic antioxidants have demonstrated encouraging results in animal models of MS but were ineffective in the completed clinical trials.Novel mitochondria-targeted antioxidants could be promising components of combined programs for MS therapy considering that they can be applied at extremely low doses and concurrently demonstrate anti-inflammatory and neuroprotective activities.
Pub.: 18 Mar '17, Pinned: 06 Mar '18
Abstract: The neuron is the target of inflammatory demyelinating processes in multiple sclerosis (MS). In progressive MS, however, there is a gathering body of evidence indicating that molecular changes converge on mitochondria within neuronal cell bodies. The most reproducible change relates to mitochondrial respiratory chain complex deficiency, which compromises the capacity of neurons to generate ATP. The resulting energy failure state is coupled with an increase in demand for energy by the demyelinated axon, being particularly relevant to the long tracts such as corticospinal tracts with long projection axons. Recent work in our laboratory and that of our collaborators indicates the limited reflection of the mitochondria changes within neurons in experimental disease models. The mitochondrial changes within neuronal compartments are likely to offer novel targets for the improvement in neuronal function in patients with progressive MS. This article is protected by copyright. All rights reserved.
Pub.: 18 Feb '18, Pinned: 06 Mar '18
Abstract: Endoplasmic reticulum (ER) stress is a hallmark of neurodegenerative diseases such as multiple sclerosis (MS). However, this physiological mechanism has multiple manifestations that range from impaired clearance of unfolded proteins to altered mitochondrial dynamics and apoptosis. While connections between the triggering of the unfolded protein response (UPR) and downstream mitochondrial dysfunction are poorly understood, the membranous contacts between the ER and mitochondria, called the mitochondria-associated membrane (MAM), could provide a functional link between these two mechanisms. Therefore, we investigated whether the guanosine triphosphatase (GTPase) Rab32, a known regulator of the MAM, mitochondrial dynamics, and apoptosis, could be associated with ER stress as well as mitochondrial dysfunction.We assessed Rab32 expression in MS patient and experimental autoimmune encephalomyelitis (EAE) tissue, via observation of mitochondria in primary neurons and via monitoring of survival of neuronal cells upon increased Rab32 expression.We found that the induction of Rab32 and other MAM proteins correlates with ER stress proteins in MS brain, as well as in EAE, and occurs in multiple central nervous system (CNS) cell types. We identify Rab32, known to increase in response to acute brain inflammation, as a novel unfolded protein response (UPR) target. High Rab32 expression shortens neurite length, alters mitochondria morphology, and accelerates apoptosis/necroptosis of human primary neurons and cell lines.ER stress is strongly associated with Rab32 upregulation in the progression of MS, leading to mitochondrial dysfunction and neuronal death.
Pub.: 25 Jan '17, Pinned: 06 Mar '18