BKCa (Slo) Channel Regulates Mitochondrial Function and Lifespan in Drosophila melanogaster

BKCa channels, originally discovered in Drosophila melanogaster as slowpoke (slo), are recognized for their roles in cellular and organ physiology. Pharmacological approaches implicated BKCa channels in cellular and organ protection possibly for their ability to modulate mitochondrial function. However, the direct role of BKCa channels in regulating mitochondrial structure and function is not deciphered. Here, we demonstrate that BKCa channels are present in fly mitochondria, and slo mutants show structural and functional defects in mitochondria. slo mutants display an increase in reactive oxygen species and the modulation of ROS affected their survival. We also found that the absence of BKCa channels reduced the lifespan of Drosophila, and overexpression of human BKCa channels in flies extends life span in males. Our study establishes the presence of BKCa channels in mitochondria of Drosophila and ascertains its novel physiological role in regulating mitochondrial structural and functional integrity, and lifespan.

[1]  S. Goswami,et al.  Expression and Activation of BKCa Channels in Mice Protects Against Ischemia-Reperfusion Injury of Isolated Hearts by Modulating Mitochondrial Function , 2019, Front. Cardiovasc. Med..

[2]  A. Hsu,et al.  Genetic and pharmacological interventions in the aging motor nervous system slow motor aging and extend life span in C. elegans , 2019, Science Advances.

[3]  A. Szewczyk,et al.  cGMP-Elevating Compounds and Ischemic Conditioning Provide Cardioprotection Against Ischemia and Reperfusion Injury via Cardiomyocyte-Specific BK Channels , 2017, Circulation.

[4]  M. Bottomley,et al.  Survival and growth of C57BL/6J mice lacking the BK channel, Kcnma1: lower adult body weight occurs together with higher body fat , 2017, Physiological reports.

[5]  N. Zhang,et al.  4E-BP is a target of the GCN2–ATF4 pathway during Drosophila development and aging , 2017, The Journal of cell biology.

[6]  E. Stefani,et al.  MaxiK channel interactome reveals its interaction with GABA transporter 3 and heat shock protein 60 in the mammalian brain , 2016, Neuroscience.

[7]  V. Pell,et al.  Moving Forwards by Blocking Back-Flow: The Yin and Yang of MI Therapy. , 2016, Circulation research.

[8]  Alex Zhavoronkov,et al.  Lifespan and Stress Resistance in Drosophila with Overexpressed DNA Repair Genes , 2015, Scientific Reports.

[9]  J. Meijer,et al.  Age-related changes in large-conductance calcium-activated potassium channels in mammalian circadian clock neurons , 2015, Neurobiology of Aging.

[10]  E. Stefani,et al.  MaxiK channel and cell signalling , 2014, Pflügers Archiv - European Journal of Physiology.

[11]  R. Strong,et al.  Ligand binding‐dependent functions of the lipocalin NLaz: an in vivo study in Drosophila , 2014, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[12]  Fabio Demontis,et al.  Whole-mount immunostaining of Drosophila skeletal muscle , 2013, Nature Protocols.

[13]  A. Szewczyk,et al.  Putative Structural and Functional Coupling of the Mitochondrial BKCa Channel to the Respiratory Chain , 2013, PloS one.

[14]  E. Stefani,et al.  mitoBKCa is encoded by the Kcnma1 gene, and a splicing sequence defines its mitochondrial location , 2013, Proceedings of the National Academy of Sciences.

[15]  A. Szewczyk,et al.  Large-conductance Ca²⁺-activated potassium channel in mitochondria of endothelial EA.hy926 cells. , 2013, American journal of physiology. Heart and circulatory physiology.

[16]  Ravikumar Hosamani.  Acute exposure of Drosophila melanogaster to paraquat causes oxidative stress and mitochondrial dysfunction. , 2013, Archives of insect biochemistry and physiology.

[17]  Jianfeng Liu,et al.  A Genetic Program Promotes C. elegans Longevity at Cold Temperatures via a Thermosensitive TRP Channel , 2013, Cell.

[18]  D. Walker,et al.  Intestinal barrier dysfunction links metabolic and inflammatory markers of aging to death in Drosophila , 2012, Proceedings of the National Academy of Sciences.

[19]  E. Stefani,et al.  Intracellular BKCa (iBKCa) channels , 2012, The Journal of physiology.

[20]  M. Guo.  Drosophila as a model to study mitochondrial dysfunction in Parkinson's disease. , 2012, Cold Spring Harbor perspectives in medicine.

[21]  C. Nichols,et al.  Methods to assay Drosophila behavior. , 2012, Journal of visualized experiments : JoVE.

[22]  E. Stefani,et al.  Visualization and quantification of cardiac mitochondrial protein clusters with STED microscopy. , 2012, Mitochondrion.

[23]  M. Grotewiel,et al.  Drosophila as a model for age-related impairment in locomotor and other behaviors , 2011, Experimental Gerontology.

[24]  David W. Walker,et al.  The Role of Mitochondria in Drosophila Aging , 2011, Experimental Gerontology.

[25]  L. Scorrano,et al.  During autophagy mitochondria elongate, are spared from degradation and sustain cell viability , 2011, Nature Cell Biology.

[26]  N. Perrimon,et al.  FOXO/4E-BP Signaling in Drosophila Muscles Regulates Organism-wide Proteostasis during Aging , 2010, Cell.

[27]  C. Montell,et al.  Drosophila TRPA1 Channel Is Required to Avoid the Naturally Occurring Insect Repellent Citronellal , 2010, Current Biology.

[28]  K. Ocorr,et al.  Dystrophin deficiency in Drosophila reduces lifespan and causes a dilated cardiomyopathy phenotype , 2008, Aging cell.

[29]  Antonia P. Sagona,et al.  Ref(2)P, the Drosophila melanogaster homologue of mammalian p62, is required for the formation of protein aggregates in adult brain , 2008, The Journal of cell biology.

[30]  I. Boros,et al.  Daxx-like Protein of Drosophila Interacts with Dmp53 and Affects Longevity and Ark mRNA Level* , 2007, Journal of Biological Chemistry.

[31]  F. Muller,et al.  Trends in oxidative aging theories. , 2007, Free radical biology & medicine.

[32]  Satpal Singh,et al.  Mutations in Cytochrome c Oxidase Subunit VIa Cause Neurodegeneration and Motor Dysfunction in Drosophila , 2007, Genetics.

[33]  S. Kay,et al.  Impaired clock output by altered connectivity in the circadian network , 2007, Proceedings of the National Academy of Sciences.

[34]  R. Balaban,et al.  Modeling mitochondrial function. , 2006, American journal of physiology. Cell physiology.

[35]  R. Lodi,et al.  Friedreich's ataxia: from disease mechanisms to therapeutic interventions. , 2006, Antioxidants & redox signaling.

[36]  E. Stefani,et al.  MaxiK channel partners: physiological impact , 2006, The Journal of physiology.

[37]  K. Nair,et al.  Decline in skeletal muscle mitochondrial function with aging in humans. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[38]  I. Condò,et al.  Reduced expression of frataxin extends the lifespan of Caenorhabditis elegans , 2005, Aging cell.

[39]  Robert S. Balaban,et al.  Mitochondria, Oxidants, and Aging , 2005, Cell.

[40]  E. Stefani,et al.  Functional and molecular evidence of MaxiK channel β1 subunit decrease with coronary artery ageing in the rat , 2004, The Journal of physiology.

[41]  R. Aldrich,et al.  Overactive Bladder and Incontinence in the Absence of the BK Large Conductance Ca2+-activated K+ Channel* , 2004, Journal of Biological Chemistry.

[42]  S. Benzer,et al.  Mitochondrial "swirls" induced by oxygen stress and in the Drosophila mutant hyperswirl. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[43]  A. B. Maunsbach,et al.  Biological ultrastructure research; the first 50 years. , 2004, Tissue & cell.

[44]  C. Bruno,et al.  Respiratory complex III is required to maintain complex I in mammalian mitochondria. , 2004, Molecular cell.

[45]  Melani-Ivy Samson,et al.  Overexpression of the small mitochondrial Hsp22 extends Drosophila life span and increases resistance to oxidative stress , 2004, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[46]  Yongge Liu,et al.  Cytoprotective Role of Ca2+- Activated K+ Channels in the Cardiac Inner Mitochondrial Membrane , 2002, Science.

[47]  LigiaToro,et al.  Decreased Expression of Voltage- and Ca2+-Activated K+ Channels in Coronary Smooth Muscle During Aging , 2001 .

[48]  E. Stefani,et al.  Decreased Expression of Voltage- and Ca 2 1 -Activated K 1 Channels in Coronary Smooth Muscle During Aging , 2001 .

[49]  J. Melki,et al.  Mouse models for Friedreich ataxia exhibit cardiomyopathy, sensory nerve defect and Fe-S enzyme deficiency followed by intramitochondrial iron deposits , 2001, Nature Genetics.

[50]  J. L. Larimer,et al.  Molecular Separation of Two Behavioral Phenotypes by a Mutation Affecting the Promoters of a Ca-Activated K Channel , 2000, The Journal of Neuroscience.

[51]  J. Borecký,et al.  Ca2+-activated K channel of the BK-type in the inner mitochondrial membrane of a human glioma cell line. , 1999, Biochemical and biophysical research communications.

[52]  S. Benzer,et al.  Extended life-span and stress resistance in the Drosophila mutant methuselah. , 1998, Science.

[53]  R. S. Sohal,et al.  Extension of life-span by overexpression of superoxide dismutase and catalase in Drosophila melanogaster. , 1994, Science.

[54]  N. Atkinson,et al.  A component of calcium-activated potassium channels encoded by the Drosophila slo locus. , 1991, Science.

[55]  M. Saito,et al.  Expression of ion channels and mutational effects in giant Drosophila neurons differentiated from cell division-arrested embryonic neuroblasts , 1991, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[56]  Satpal Singh,et al.  Mutational and gene dosage analysis of calcium-activated potassium channels in Drosophila: Correlation of micro- and macroscopic currents , 1990, Neuron.

[57]  Satpal Singh,et al.  Complete separation of four potassium currents in drosophila , 1989, Neuron.

[58]  L. Partridge,et al.  A cost of mating in female fruitflies , 1989, Nature.

[59]  B. Ganetzky,et al.  A Drosophila mutation that eliminates a calcium-dependent potassium current. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[60]  Osvaldo Alvarez,et al.  Molecular Determinants of BK Channel Functional Diversity and Functioning. , 2017, Physiological reviews.

[61]  Harpreet Singh,et al.  Anion Channels of Mitochondria. , 2017, Handbook of experimental pharmacology.

[62]  W. Orr,et al.  Mitochondrial peroxiredoxins are essential in regulating the relationship between Drosophila immunity and aging. , 2017, Biochimica et biophysica acta. Molecular basis of disease.

[63]  A. Szewczyk,et al.  CALL FOR PAPERS Mitochondria in Cardiovascular Physiology and Disease Large-conductance Ca 2 -activated potassium channel in mitochondria of endothelial EA.hy926 cells , 2013 .

[64]  E. Gnaiger,et al.  High-resolution respirometry: OXPHOS protocols for human cells and permeabilized fibers from small biopsies of human muscle. , 2012, Methods in molecular biology.

[65]  H. Park.  Genetic analysis of the Drosophila slowpoke gene and development of a novel method of targeted downregulation of gene expression by Gal4 -repressor , 2009 .

[66]  E. Stefani,et al.  Aging, ion channel expression, and vascular function. , 2002, Vascular pharmacology.