Kambiz Alavian, PhD
Research & Publications
Biography
Research Summary
The research in my laboratory revolves around the central theme of mitochondrial bioenergetic efficiency. The processes of ATP synthesis through oxidative phosphorylation and mitochondrial substrate production for anabolic growth both require an electrochemical (proton) gradient across the mitochondrial inner membrane. The proton gradient is produced as a result of redox reactions by the electron transport chain (ETC). Futile ion leak currents across the inner membrane impede ATP production by the mitochondrial F1Fo ATP synthase as well as the passive and active transport of substrates, including pyruvate, phosphate and glutamate into the mitochondrial matrix. The leak currents, therefore, not only cause inefficiency in energy production, they may also interfere with cellular growth by limiting mitochondrial substrate levels required for downstream anabolic processes. In recent years, we have found that this process is regulated by a number of neuroprotective oncogenes. The goal of research in my laboratory is to continue to understand the basic molecular mechanisms, including serine metabolism, involved in mitochondrial energetic efficiency and the connections between this process to proliferation of adult and pediatric brain tumor cells and neuronal physiology. We will also pursue the results of our recent drug discovery project to develop novel compounds for modulation of mitochondrial ion leak currents for treatment of glioblastoma multiforme (GBM) and diffuse intrinsic pontine glioma (DIPG).
Extensive Research Description
Neuronal metabolic plasticity
The efficient regulation of cellular energy production by mitochondria is dependent upon the integrity of the inner and outer mitochondrial membranes and the maintenance of the proton-motive force that drives the production of adenosine triphosphate (ATP) by the F1Fo ATP synthase complex. The proton gradient produced as a function of the activity of mitochondrial electron transport chain is also required for pumping of cations, including sodium and potassium from matrix, as well as passive and active transport of substrates, required for cellular and synaptic growth, repair and regeneration across the inner membrane. Under physiological conditions mitochondrial membranes contain a number of ion conductance pathways, including proton leak (uncoupling) currents, which comprise a major energy sink (up to 50% in healthy tissue). While baseline leak currents exist in healthy tissue, some conductance pathways seem to be functionally expressed or suppressed only under pathophysiological conditions. Mitochondrial dysfunction through increased activity of the ion leak channels is particularly problematic in neurons, which have exceptional energy requirements. Neurons require the physical translocation of mitochondria along axons and dendrites to synapses, providing numerous additional opportunities for disruption of critical energy supplies. Neuronal mitochondrial stress, as a result of trauma, aging and adverse environmental or genetic factors, would result in increased risk for degeneration and loss of the energetic capacity for growth, repair and regeneration. We have described an ion leak channel associated with the F1Fo ATP synthase that is activated by calcium or ROS and is regulated by the anti-apoptotic member of the Bcl-2 family, Bcl-xL. In my laboratory we have been investigating the molecular interactions that contribute to this mechanism of mitochondrial bioenergetic efficiency.
- The role of Parkinson’s disease gene DJ1 in modulation of neuronal energy metabolism. We have recently identified the early onset Parkinson’s disease gene DJ1 (PARK7) as a modulator of neuronal metabolic efficiency through direct interaction with the mitochondrial F1Fo ATP synthase. We have also found that the DJ1 associated regulatory complex is disrupted by the PD-associated mutations, resulting in reduced mitochondrial efficiency. The adequate levels of DJ1 are required at mitochondria to meet locally increased ATP demand under stress or intense neuronal and synaptic activity. Our unpublished data also demonstrate that the 14-3-3 protein is the main regulator of the subcellular localization and the bioenergetic functions of DJ1. We are currently characterizing the effect of this novel function of DJ1 and 14-3-3 on the bioenergetics of resting, active and degenerating neurons through measurements of cellular ATP levels, oxygen consumption and metabolomics studies.
- The role of Bcl-xL in long-term synaptic potentiation. Synaptic potentiation produces larger and more frequently firing synapses that have higher metabolic demands compared to resting synapses. Our previous work has demonstrated that even in the absence of high frequency stimulation, over-expression of the anti-apoptotic molecule, Bcl-xL, increases the number and size of synapses, localizes mitochondria to presynaptic sites, increases mitochondrial biomass, and enhances ATP production. Our unpublished data have shown that Bcl-xL is crucial for events that ready the synapse for long-term potentiation (LTP), as Bcl-xL overexpression increases the number of resting GluR1 AMPA receptors. Bcl-xL overexpression increases the amplitude of mEPSCs, consistent with a role for Bcl-xL in increasing responses to spontaneous transmitter release through effects on postsynaptic AMPA receptor insertion. The aim of this project is to test the novel hypothesis that Bcl-xL interacts with the mitochondrial ATP synthase to close the inner membrane proton leak during high intensity synaptic stimulation. This will enhance mitochondrial metabolic efficiency in a long-lasting fashion. In aging and in neurodegenerative conditions, a decline in mitochondrial function has been correlated with decreased neuronal and synaptic function followed by a progressive neuronal loss.
- The connection between the degeneration of midbrain dopaminergic neurons and mitochondrial energy production. The selective degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) is the pathological hallmark of Parkinson’s disease. The dopaminergic neurons in the neighbouring ventral tegmental area (VTA) are relatively resistant to cell death. Several groups have characterized the gene/protein expression profile of the SNpc vs. VTA neurons. A number of differentially expressed proteins localize to mitochondria. There is also evidence that the mitochondria of the two types of dopaminergic neurons are different in their membrane potential and function. This project aims to identify the mitochondrial processes that contribute to vulnerability of SNpc neurons by comparing them to their VTA counterparts and to determine whether instability in the mitochondrial membrane potential predisposes neurons to degeneration.
- Mitochondrial control of protein translation in Fragile X. We have found that fragile X mental retardation protein (FMRP) localizes to the mitochondria and that enhanced mitochondrial efficiency reverses the defect in protein translation in mouse and human models of FX. We have also found that Bcl-xL represses protein translation, similarly to FMRP, in a similar manner to or in collaboration with FMRP to increase oxidative metabolism acutely during stimulus dependent synaptogenesis. We have employed ATP measurements, mitochondrial ion channel recordings, and single synapse oxygen consumption studies to characterise the role of mitochondrial efficiency in protein translation. The failure to increase the use of oxidative metabolism by synapses during development or plasticity seems to contribute to abnormal synaptic phenotypes and abnormal synaptic function as illustrated by Fmr1-/y mutant animals. We predict that rescuing these mitochondrial metabolic defects by pharmacological treatment or genetic ATP synthase channel modulation will normalize protein translation levels, synaptic phenotypes and behavior in the Fmr1-/y mutant mouse. In particular, we are planning to test the effect of the candidate drugs that modulate the metabolic efficiency of the mitochondria (see Theme 3) in Fmr1-/y mutant mice.
Mitochondrial efficiency and proliferation of adult and pediatric brain tumors
Resistance to cell death and reprogramming of energy metabolism are two prominent features of cancer cells. Mitochondria are known to be intimately linked to both these features and are believed to play a key role in a diversity of processes contributing to the metabolic plasticity and growth of cancer cells. While most of the energy of normal cells is provided by mitochondrial oxidative phosphorylation (OXPHOS), under normoxic or hypoxic conditions many cancer cell types obtain a major portion of their cellular ATP through glycolysis, a less efficient means of energy production. In such cells typically 40 to 60% of ATP generation may occur via glycolysis and mitochondria generate the remainder of the energy requirements. Mitochondrial substrates are also utilized in tumour cells for anabolic growth. The process of ATP production through OXPHOS and substrates production for anabolic growth both require generation of an electrochemical gradient across the mitochondrial inner membrane. Ion leak currents across the inner membrane, therefore, impede ATP production and slow down exchange of substrates required for proliferation and growth (Figure-1). The complete loss of membrane potential through the opening of the mitochondrial permeability transition pore may ultimately result in cell death.
- The role of mitochondrial metabolic efficiency in proliferation of brain tumor cells. A metabolic shift from mitochondrial OXPHOS toward aerobic glycolysis is believed to be a prominent feature of many cancer cell types. This feature of cancer cells, however, is not universal and the degree to which the tumour cells rely on different means of energy production is highly variable. We recently compared the metabolic profile of low-grade (astrocytoma) to the high-grade glioma cells (including GBM and DIPG) by performing metabolomics, gene expression analysis and biochemical studies. We found that while glycolysis is highly active in both grade 3 and grade 4 cell types, the glioma (grade 4) cells also rely heavily on their mitochondria for ATP production and for anabolic processes. We also demonstrated that this process involves enhanced mitochondrial coupling and efficiency in ATP synthesis through closure of the inner membrane leak channels. We are currently examining the source of the leak currents.
- The connection between serine metabolism and the TCA cycle Anaplerosis. In addition to modulation of ATP production efficiency, the mitochondrial ion leak channel regulate the exchange of ions and substrates including pyruvate and glutamate across the inner membrane. These substrates are utilized for not only ATP production but for maintaining the TCA cycle anaplerotic flux required for biosynthesis of lipids, amino acids and nucleotides. Through a metabolomics study we have demonstrated an inverse correlation between the rate of serine metabolism and the mitochondrial pyruvate and glutamate uptake. Our data indicates that the grade 3 astrocytoma cells, with a low rate of proliferation, have a higher rate of serine and glycine metabolism in comparison to their grade 4 counterparts. The decrease in serine metabolism is mainly due to downregulation of a key enzyme phosphohydroxythreonine aminotransferase in the grade 4 glioma cells. The downregulation of serine metabolism in turn leads to upregulation of pyruvate production. The excess pyruvate is utilized by mitochondria for ATP production and for the biosynthetic processes required for proliferation. Since the mitochondrial pyruvate uptake depends on the mitochondrial membrane potential, modulation of the ion leak channels would change the growth rate of the glioblastoma cells. We are currently investigating this concept for development of novel therapeutics for treatment of glioblastoma multiforme tumors.
Coauthors
Research Interests
Glioblastoma; Ion Channels; Metabolism; Mitochondria; Neuronal Plasticity; Neurosciences; Parkinson Disease; Stem Cells; Developmental Biology; Neurodegenerative Diseases; Deep Brain Stimulation
Research Image
Lab theme figure (simple)-01
Selected Publications
- CAV2.3 expression is upregulated in the substantia nigra pars compacta of humans with Parkinson's diseaseSharifi P, Bae H, Gveric D, Gentleman S, Smith P, Tierney T, Alavian K. CAV2.3 expression is upregulated in the substantia nigra pars compacta of humans with Parkinson's disease. Brain Disorders 2022, 5: 100031. DOI: 10.1016/j.dscb.2022.100031.
- Initial experience with magnetic resonance-guided focused ultrasound stereotactic surgery for central brain lesions in young adults.Tierney T, Alavian K, Altman N, Bhatia S, Duchowny M, Hyslop A, Jayakar P, Resnick T, Wang S, Miller I, Ragheb J. Initial experience with magnetic resonance-guided focused ultrasound stereotactic surgery for central brain lesions in young adults. Journal Of Neurosurgery 2022, 137: 1-8. PMID: 35171812, DOI: 10.3171/2021.10.jns21416.
- Threshold Concepts in Neuroscience: Identification Challenges, Educational Opportunities and Recommendations for PracticeSandrone S, Alavian K. Threshold Concepts in Neuroscience: Identification Challenges, Educational Opportunities and Recommendations for Practice. Frontiers In Education 2021, 5: 540307. DOI: 10.3389/feduc.2020.540307.
- The factors for the early and late development of midbrain dopaminergic neurons segregate into two distinct evolutionary clustersNiu Y, Moghimyfiroozabad S, Moghimyfiroozabad A, Tierney T, Alavian K. The factors for the early and late development of midbrain dopaminergic neurons segregate into two distinct evolutionary clusters. Brain Disorders 2021, 1: 100002. DOI: 10.1016/j.dscb.2021.100002.
- Disorders of the brain, paradoxes of the enigmaAlavian K, Yu J. Disorders of the brain, paradoxes of the enigma. Brain Disorders 2021, 1: 100003. DOI: 10.1016/j.dscb.2021.100003.
- Mitochondrial (ATP Synthase) Permeability Transition PoreJonas E, Mnatsakanyan N, Alavian K, Chen R. Mitochondrial (ATP Synthase) Permeability Transition Pore. Biophysical Journal 2020, 118: 16a. DOI: 10.1016/j.bpj.2019.11.269.
- Post mortem examination of Parkinson's disease brains suggests decline in mitochondrial biomass, reversed by deep brain stimulation of subthalamic nucleusMallach A, Weinert M, Arthur J, Gveric D, Tierney TS, Alavian KN. Post mortem examination of Parkinson's disease brains suggests decline in mitochondrial biomass, reversed by deep brain stimulation of subthalamic nucleus. The FASEB Journal 2019, 33: 6957-6961. PMID: 30862197, DOI: 10.1096/fj.201802628r.
- The Mitochondrial Permeability Transition Pore: Molecular Structure and Function in Health and DiseaseJonas E, Porter G, Beutner G, Mnatsakanyan N, Park H, Mehta N, Chen R, Alavian K. The Mitochondrial Permeability Transition Pore: Molecular Structure and Function in Health and Disease. 2017, 69-105. DOI: 10.1007/978-3-319-55539-3_3.
- Mitochondria and Memory: Bioenergetics, Synaptic Plasticity and NeurodegenerationJonas E, Mnatsakanyan N, Miranda P, Park H, Chen R, Licznerski P, Weinert M, Smith P, Chavez A, Zukin R, Gribkoff V, Alavian K. Mitochondria and Memory: Bioenergetics, Synaptic Plasticity and Neurodegeneration. Biophysical Journal 2017, 112: 180a. DOI: 10.1016/j.bpj.2016.11.996.
- The Mitochondrial Permeability Transition Pore and ATP SynthaseBeutner G, Alavian K, Jonas EA, Porter GA. The Mitochondrial Permeability Transition Pore and ATP Synthase. 2016, 240: 21-46. PMID: 27590224, PMCID: PMC7439278, DOI: 10.1007/164_2016_5.
- PTP and LTP: The physiological role of the permeability transition pore in learning and memoryJonas E, Miranda P, Gribkoff V, Alavian K, Park H, Wu J, Chavez A, Zukin R, Hardwick J, Mnatsakanyan N. PTP and LTP: The physiological role of the permeability transition pore in learning and memory. Biochimica Et Biophysica Acta (BBA) - Bioenergetics 2016, 1857: e66-e67. DOI: 10.1016/j.bbabio.2016.04.357.
- The Mitochondrial Permeability Transition Pore, the c‐Subunit of the F1Fo ATP Synthase, Cellular Development, and Synaptic EfficiencyJonas E, Porter G, Beutner G, Mnatsakanyan N, Alavian K. The Mitochondrial Permeability Transition Pore, the c‐Subunit of the F1Fo ATP Synthase, Cellular Development, and Synaptic Efficiency. 2015, 31-64. DOI: 10.1002/9781119017127.ch2.
- ABT‐737 Inhibits Full Length And Cleaved Pro‐Apoptotic Bcl‐xL, Resulting in Differential Effects on Death And SurvivalPark H, Licznerski P, Niu Y, Alavian K, Jonas E. ABT‐737 Inhibits Full Length And Cleaved Pro‐Apoptotic Bcl‐xL, Resulting in Differential Effects on Death And Survival. The FASEB Journal 2015, 29 DOI: 10.1096/fasebj.29.1_supplement.777.4.
- Analysis of Gene Expression Changes in the Rat Hippocampus After Deep Brain Stimulation of the Anterior Thalamic NucleusSelvakumar T, Alavian K, Tierney T. Analysis of Gene Expression Changes in the Rat Hippocampus After Deep Brain Stimulation of the Anterior Thalamic Nucleus. Journal Of Visualized Experiments 2015 DOI: 10.3791/52457-v.
- Isolation, Culture and Long-Term Maintenance of Primary Mesencephalic Dopaminergic Neurons From Embryonic Rodent BrainsWeinert M, Selvakumar T, Tierney T, Alavian K. Isolation, Culture and Long-Term Maintenance of Primary Mesencephalic Dopaminergic Neurons From Embryonic Rodent Brains. Journal Of Visualized Experiments 2015 DOI: 10.3791/52475-v.
- The C-Subunit of the ATP Synthase Forms the Pore of the PTPJonas E, Sacchetti S, Park H, Lazrove E, Beutner G, Porter G, Alavian K. The C-Subunit of the ATP Synthase Forms the Pore of the PTP. Biophysical Journal 2014, 106: 3a-4a. DOI: 10.1016/j.bpj.2013.11.049.
- A Bcl-xL–Drp1 complex regulates synaptic vesicle membrane dynamics during endocytosisLi H, Alavian KN, Lazrove E, Mehta N, Jones A, Zhang P, Licznerski P, Graham M, Uo T, Guo J, Rahner C, Duman RS, Morrison RS, Jonas EA. A Bcl-xL–Drp1 complex regulates synaptic vesicle membrane dynamics during endocytosis. Nature Cell Biology 2013, 15: 773-785. PMID: 23792689, PMCID: PMC3725990, DOI: 10.1038/ncb2791.
- F1FO ATPase Vesicle Preparation and Technique for Performing Patch Clamp Recordings of Submitochondrial Vesicle MembranesSacchetti S, Alavian K, Lazrove E, Jonas E. F1FO ATPase Vesicle Preparation and Technique for Performing Patch Clamp Recordings of Submitochondrial Vesicle Membranes. Journal Of Visualized Experiments 2013 DOI: 10.3791/4394-v.
- DJ1 regulates Neuronal Mitochondrial Bioenergetic EfficiencyJonas E, Lazrove E, Nabili P, Alavian K. DJ1 regulates Neuronal Mitochondrial Bioenergetic Efficiency. Biophysical Journal 2013, 104: 657a. DOI: 10.1016/j.bpj.2012.11.3628.
- N-terminally cleaved Bcl-xL mediates ischemia-induced neuronal deathOfengeim D, Chen YB, Miyawaki T, Li H, Sacchetti S, Flannery RJ, Alavian KN, Pontarelli F, Roelofs BA, Hickman JA, Hardwick JM, Zukin RS, Jonas EA. N-terminally cleaved Bcl-xL mediates ischemia-induced neuronal death. Nature Neuroscience 2012, 15: 574-580. PMID: 22366758, PMCID: PMC3862259, DOI: 10.1038/nn.3054.
- The C-Subunit Ring of the F1FO ATP Synthase Constitutes a Leak Channel that Regulates Cellular Metabolic Efficiency by Counteracting the H+ TranslocatorAlavian K, Lazrove E, Nabili P, Li H, Jonas E. The C-Subunit Ring of the F1FO ATP Synthase Constitutes a Leak Channel that Regulates Cellular Metabolic Efficiency by Counteracting the H+ Translocator. Biophysical Journal 2012, 102: 571a. DOI: 10.1016/j.bpj.2011.11.3110.
- Erratum: Bcl-xL regulates metabolic efficiency of neurons through interaction with the mitochondrial F1FO ATP synthaseAlavian K, Li H, Collis L, Bonanni L, Zeng L, Sacchetti S, Lazrove E, Nabili P, Flaherty B, Graham M, Chen Y, Messerli S, Mariggio M, Rahner C, McNay E, Shore G, Smith P, Hardwick J, Jonas E. Erratum: Bcl-xL regulates metabolic efficiency of neurons through interaction with the mitochondrial F1FO ATP synthase. Nature Cell Biology 2011, 13: 1383-1383. DOI: 10.1038/ncb2369.
- Bcl-x L regulates mitochondrial energetics by stabilizing the inner membrane potentialChen Y, Aon M, Hsu Y, Soane L, Teng X, McCaffery J, Cheng W, Qi B, Li H, Alavian K, Dayhoff-Brannigan M, Zou S, Pineda F, O'Rourke B, Ko Y, Pedersen P, Kaczmarek L, Jonas E, Hardwick J. Bcl-x L regulates mitochondrial energetics by stabilizing the inner membrane potential. Journal Of Experimental Medicine 2011, 208: i29-i29. DOI: 10.1084/jem20811oia29.
- Bcl-xL regulates mitochondrial energetics by stabilizing the inner membrane potentialChen YB, Aon MA, Hsu YT, Soane L, Teng X, McCaffery JM, Cheng WC, Qi B, Li H, Alavian KN, Dayhoff-Brannigan M, Zou S, Pineda FJ, O'Rourke B, Ko YH, Pedersen PL, Kaczmarek LK, Jonas EA, Hardwick JM. Bcl-xL regulates mitochondrial energetics by stabilizing the inner membrane potential. Journal Of Cell Biology 2011, 195: 263-276. PMID: 21987637, PMCID: PMC3198165, DOI: 10.1083/jcb.201108059.
- Bcl-xL regulates metabolic efficiency of neurons through interaction with the mitochondrial F1FO ATP synthaseAlavian KN, Li H, Collis L, Bonanni L, Zeng L, Sacchetti S, Lazrove E, Nabili P, Flaherty B, Graham M, Chen Y, Messerli SM, Mariggio MA, Rahner C, McNay E, Shore GC, Smith PJ, Hardwick JM, Jonas EA. Bcl-xL regulates metabolic efficiency of neurons through interaction with the mitochondrial F1FO ATP synthase. Nature Cell Biology 2011, 13: 1224-1233. PMID: 21926988, PMCID: PMC3186867, DOI: 10.1038/ncb2330.
- Decrease in a Leak Conductance Associated with Mitochondrial Complex V and Improved Bioenergetic Efficiency may Underlie Cytoprotection of at-Risk Neurons by DexpramipexoleSacchetti S, Dworetzky S, Alavian K, Zhang P, Bonanni L, Signore A, Mangold J, DeMarco U, Smith P, Gribkoff V, Jonas E. Decrease in a Leak Conductance Associated with Mitochondrial Complex V and Improved Bioenergetic Efficiency may Underlie Cytoprotection of at-Risk Neurons by Dexpramipexole. Biophysical Journal 2011, 100: 459a. DOI: 10.1016/j.bpj.2010.12.2701.
- Bcl-xL Determines the Metabolic Efficiency of Neurons, through Interaction with Mitochondrial ATP SynthaseAlavian K, Li H, Sacchetti S, Nabili P, Lazrove E, Bonanni L, Smith P, Hardwick J, Jonas E. Bcl-xL Determines the Metabolic Efficiency of Neurons, through Interaction with Mitochondrial ATP Synthase. Biophysical Journal 2011, 100: 459a. DOI: 10.1016/j.bpj.2010.12.2700.
- BCL-xL Regulates ATP Synthase and Synaptic EfficiencyAlavian K, Collis L, Li H, Zeng L, Bonanni L, Rahner C, Hardwick J, Jonas E. BCL-xL Regulates ATP Synthase and Synaptic Efficiency. Biophysical Journal 2010, 98: 465a. DOI: 10.1016/j.bpj.2009.12.2527.
- Elevated P75NTR expression causes death of engrailed-deficient midbrain dopaminergic neurons by Erk1/2 suppressionAlavian KN, Sgadò P, Alberi L, Subramaniam S, Simon HH. Elevated P75NTR expression causes death of engrailed-deficient midbrain dopaminergic neurons by Erk1/2 suppression. Neural Development 2009, 4: 11. PMID: 19291307, PMCID: PMC2667502, DOI: 10.1186/1749-8104-4-11.
- Transcriptional regulation of mesencephalic dopaminergic neurons: The full circle of life and deathAlavian KN, Scholz C, Simon HH. Transcriptional regulation of mesencephalic dopaminergic neurons: The full circle of life and death. Movement Disorders 2008, 23: 319-328. PMID: 18044702, DOI: 10.1002/mds.21640.
- Slow progressive degeneration of nigral dopaminergic neurons in postnatal Engrailed mutant miceSgadò P, Albéri L, Gherbassi D, Galasso SL, Ramakers GM, Alavian KN, Smidt MP, Dyck RH, Simon HH. Slow progressive degeneration of nigral dopaminergic neurons in postnatal Engrailed mutant mice. Proceedings Of The National Academy Of Sciences Of The United States Of America 2006, 103: 15242-15247. PMID: 17015829, PMCID: PMC1622807, DOI: 10.1073/pnas.0602116103.