• Arvo (3rd floor), Arvo Ylpön katu 34, 33520 Tampere, Finland
 
 
 
 
 

Howy Jacobs

Howy4

 

People

Publications

 

 

 

 

 

 

Projects

  • Maintenance
    Mitochondrial DNA replication and disease
  • Models
    Nuclear-mitochondrial interactions in Drosophila
  • Alternatives
    Alternative respiratory chain enzymes: a possible therapy for mitochondrial disorders?

Mitochondrial DNA replication and disease

A variety of human diseases, ranging from devastating conditions of infancy through to degenerative disorders seen mainly in old age, are associated with genetic lesions of mitochondrial DNA. In order to understand how mtDNA maintenance shapes cell physiology, and elucidate how it can go wrong in disease and ageing, we are studying the fundamental mechanisms of DNA replication in model organisms, using a combination of genetic and biochemical approaches.

  • Our recent findings support the so-called bootlace model of mtDNA replication, in which preformed transcripts are incorporated into replication intermediates, to create a provisional lagging-strand.
  • Consistent with this model, but with slightly different kinetics than in mammalian systems, mtDNA replication in Drosophila depends upon the stoichiometrically appropriate binding of proteins of the mitochondrial transcription termination (MTERF) family.
  • RNaseH1 is required for mtDNA maintenance in both mammals and flies. In mammals, its absence results in failure to remove the replication primers, which blocks future replication rounds.  Current work in Drosophila aims to determine whether RNaseH1 also plays additional roles in mtDNA replication.
  • In C. elegans, where mtDNA replication occurs only in the female germline, we find a signature of rolling-circle replication.
  • A fully functional ATP synthase complex is required for mtDNA maintenance in Drosophila

Kemppainen E, George J, Garipler G, Tuomela T, Kiviranta E, Soga T, Dunn CD, Jacobs HT (2016) Mitochondrial Dysfunction Plus High-Sugar Diet Provokes a Metabolic Crisis That Inhibits Growth. PLoS One 2016 ;11(1)e0145836

Syrjänen L, Valanne S, Kuuslahti M, Tuomela T, Sriram A, Sanz A, Jacobs HT, Rämet M, Parkkila S (2015) β carbonic anhydrase is required for female fertility in Drosophila melanogaster. Front Zool 2015 ;1219

Holmes JB, Akman G, Wood SR, Sakhuja K, Cerritelli SM, Moss CF, Bowmaker MR, Jacobs HT, Crouch RJ, Holt IJ (2015) Primer retention owing to the absence of RNase H1 is catastrophic for mitochondrial DNA replication. Proc Natl Acad Sci USA (in press)

Lewis SC, Joers P, Willcox S, Griffith JD, Jacobs HT, Hyman BC (2015) A rolling circle replication mechanism produces multimeric lariats of mitochondrial DNA in Caenorhabditis elegans. PLoS Genet. 11: e1004985. doi: 10.1371/journal.pgen.1004985

Fukuoh A, Cannino G, Gerards M, Buckley S, Kazancioglu S, Scialo F, Lihavainen E, Ribeiro A, Dufour E, Jacobs HT (2014) Screen for mitochondrial DNA copy number maintenance genes reveals essential role for ATP synthase. Mol Syst Biol. 10: 734. doi: 10.15252/msb.20145117.

Holt IJ, Jacobs HT (2014) Unique features of DNA replication in mitochondria: a functional and evolutionary perspective. Bioessays 36: 1024-1031. doi: 10.1002/bies.201400052.

Jõers P, Lewis SC, Fukuoh A, Parhiala M, Ellilä S, Holt IJ, Jacobs HT (2013) Mitochondrial transcription terminator family members mTTF and mTerf5 have opposing roles in coordination of mtDNA synthesis. PLoS Genet. 9: e1003800. doi: 10.1371/journal.pgen.1003800.

Reyes A, Kazak L, Wood SR, Yasukawa T, Jacobs HT, Holt IJ (2013) Mitochondrial DNA replication proceeds via a 'bootlace' mechanism involving the incorporation of processed transcripts. Nucleic Acids Res. 41: 5837-5850. doi: 10.1093/nar/gkt196

Key collaborators: Ian Holt (London)

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Nuclear-mitochondrial interactions in Drosophila

We use various Drosophila mutants with defects in mitochondrial function to analyse the contributions of nuclear and mitochondrial genotype, as well as environmental factors such as diet and exposure to antibiotics, to organismal phenotype.  Much of our attention has been focussed on the tko25t strain, which carries a point mutation in the gene for mitoribosomal protein S12, and is a useful model for studying human mitochondrial disease. We are also studying the roles in animal development of global regulators of mitochondrial function, and the physiological effects of respiratory chain dysfunction in the nervous system, using flies as a model system.

  • Altered gene expression and metabolite profiles in tko25t indicate reliance on glycolysis, but concomitant build-up of potentially toxic intermediates such as pyruvate and lactate, as well as depletion of ATP and profound redox disturbances
  • The tko25t mutant phenotype can be partially alleviated by specific mitochondrial backgrounds in cybrid flies, and is also be susceptible to manipulations of the nuclear genome.
  • The sesB1 mutant, affecting the major isoform of the adenine nucleotide translocase, shares many features with tko25t. Its phenotype is also subject to modification by genetic background, but in subtly different ways.
  • On-going work on the contribution of mtDNA genotype to the phenotype of tko25t is a joint project with Finland Distinguished Professor Laurie Kaguni (Tampere, Michigan State).

Vartiainen S, Chen S, George J, Tuomela T, Luoto KR, O'Dell KM, Jacobs HT (2014). Phenotypic rescue of a Drosophila model of mitochondrial ANT1 disease. Dis Model Mech. 7: 635-648. doi: 10.1242/dmm.016527

Kemppainen KK, Kemppainen E, Jacobs HT (2014) The alternative oxidase AOX does not rescue the phenotype of tko25t mutant flies. G3 (Bethesda) 4: 2013-2021. doi: 10.1534/g3.114.013946

A cytoplasmic suppressor of a nuclear mutation affecting mitochondrial functions in Drosophila. Chen S, Oliveira MT, Sanz A, Kemppainen E, Fukuoh A, Schlicht B, Kaguni LS, Jacobs HT (012). Genetics. 192 483-493. doi: 10.1534/genetics.112.143719

Kemppainen E, Fernández-Ayala DJ, Galbraith LC, O'Dell KM, Jacobs HT (2009) Phenotypic suppression of the Drosophila mitochondrial disease-like mutant tko(25t) by duplication of the mutant gene in its natural chromosomal context. Mitochondrion 9: 353-363. doi: 10.1016/j.mito.2009.07.002.

Fernández-Ayala DJ, Chen S, Kemppainen E, O'Dell KM, Jacobs HT (2010) Gene expression in a Drosophila model of mitochondrial disease. PLoS One 5: e8549. doi: 10.1371/journal.pone.0008549.

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Alternative respiratory chain enzymes: a possible therapy for mitochondrial disorders?

The genomes of plants, fungi and many microbes, as well as some primitive animal phyla, contain genes for alternative mitochondrial respiratory chain enzymes, which buffer a host of redox and bioenergetic stresses similar to those encountered in humans under pathological conditions. The genes for these alternative enzymes are absent from humans and other complex animals. However, we reasoned that their introduction may alleviate many of the physiological defects associated with mitochondrial disease. We have transferred the relevant genes from the tunicate Ciona, as well as from fungi, into human cells and model organisms, creating proof of concept for such protection. Our current research focuses on ascertaining the potential of these enzymes in therapy, both by exploring what specific pathologies they can prevent, as well as testing out ways to safely introduce them in a therapeutically effective form to humans. In addition we are studying the natural biology of the alternative enzymes in Ciona, to understand better how they can be most effectively used in humans.

  • The alternative oxidase (AOX) and NADH dehydrogenase (NDX) from Ciona can be expressed in model organisms in all tissues and throughout the life cycle without any significant deleterious effects.
  • AOX and NDX confer resistance against respiratory poisons (e.g. cyanide, antimycin, rotenone) on both cells and whole organisms
  • AOX protects cells and tissues form the effects of chronic exposure to mitochondrial toxins, such as found in cigarette smoke
  • NDX and AOX can protect Drosophila from lethality and other severe phenotypes caused by genetic ablation of respiratory chain complexes I and IV
  • AOX also protects against pathological insults connected to oxidative stress

Gospodaryov DV, Lushchak OV, Rovenko BM, Perkhulyn NV, Gerards M, Tuomela T, Jacobs HT (2014) Ciona intestinalis NADH dehydrogenase NDX confers stress-resistance and extended lifespan on Drosophila. Biochim Biophys Acta 1837: 1861-1869. doi: 10.1016/j.bbabio.2014.08.001

El-Khoury R, Kemppainen KK, Dufour E, Szibor M, Jacobs HT, Rustin P (2014) Engineering the alternative oxidase gene to better understand and counteract mitochondrial defects: state of the art and perspectives. Br J Pharmacol 171: 2243-2249. doi: 10.1111/bph.12570

Kemppainen KK, Rinne J, Sriram A, Lakanmaa M, Zeb A, Tuomela T, Popplestone A, Singh S, Sanz A, Rustin P, Jacobs HT (2014) Expression of alternative oxidase in Drosophila ameliorates diverse phenotypes due to cytochrome oxidase deficiency. Hum Mol Genet 23: 2078-2093.
 
El-Khoury R, Dufour E, Rak M, Ramanantsoa N, Grandchamp N, Csaba Z, Duvillié B, Bénit P, Gallego J, Gressens P, Sarkis C, Jacobs HT, Rustin P (2013) Alternative oxidase expression in the mouse enables bypassing cytochrome c oxidase blockade and limits mitochondrial ROS overproduction. PLoS Genet 9: e1003182. doi: 10.1371/journal.pgen.1003182.

Humphrey DM, Parsons RB, Ludlow ZN, Riemensperger T, Esposito G, Verstreken P, Jacobs HT, Birman S, Hirth F (2012) Alternative oxidase rescues mitochondria-mediated dopaminergic cell loss in Drosophila. Hum Mol Genet 21: 2698-2712.

Sanz A, Soikkeli M, Portero-Otín M, Wilson A, Kemppainen E, McIlroy G, Ellilä S, Kemppainen KK, Tuomela T, Lakanmaa M, Kiviranta E, Stefanatos R, Dufour E, Hutz B, Naudí A, Jové M, Zeb A, Vartiainen S, Matsuno-Yagi A, Yagi T, Rustin P, Pamplona R, Jacobs HT (2010) Expression of the yeast NADH dehydrogenase Ndi1 in Drosophila confers increased lifespan independently of dietary restriction. Proc Natl Acad Sci U S A 107: 9105-9110.

Expression of the alternative oxidase complements cytochrome c oxidase deficiency in human cells. Dassa EP, Dufour E, Gonçalves S, Paupe V, Hakkaart GA, Jacobs HT, Rustin P. EMBO Mol Med. 2009 Apr;1(1):30-6. doi: 10.1002/emmm.200900001.

Fernandez-Ayala DJ, Sanz A, Vartiainen S, Kemppainen KK, Babusiak M, Mustalahti E, Costa R, Tuomela T, Zeviani M, Chung J, O'Dell KM, Rustin P, Jacobs HT (2009) Expression of the Ciona intestinalis alternative oxidase (AOX) in Drosophila complements defects in mitochondrial oxidative phosphorylation. Cell Metab 9: 449-460. doi: 10.1016/j.cmet.2009.03.004

Key collaborators: Pierre Rustin (Paris), Thomas Braun (Bad Nauheim), Massimo Zeviani (MRC Cambridge)

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Contact information

Howy Jacobs
Academy Professor
Institute of Biotechnology
P.O.Box. 56, 00014 University of Helsinki
Street address: Viikinkaari 9, Biocenter 1
Tel. +358 50 341 2894
Fax. +358 2941 59366
e-mail: This email address is being protected from spambots. You need JavaScript enabled to view it.