The Mitochondrial Fission Protein HFis1 Requires the Endoplasmic Reticulum Gateway to Induce Apoptosis

Overview

Journal Mol Biol Cell

Specialties Cell Biology
Molecular Biology

Date 2006 Aug 18

PMID 16914522

Citations 60

Authors

Emilie Alirol

Dominic James

Denise Huber

Andrea Marchetto

Lodovica Vergani

Jean-Claude Martinou

Luca Scorrano

Affiliations

Soon will be listed here.

Abstract

Mitochondrial fission ensures organelle inheritance during cell division and participates in apoptosis. The fission protein hFis1 triggers caspase-dependent cell death, by causing the release of cytochrome c from mitochondria. Here we show that mitochondrial fission induced by hFis1 is genetically distinct from apoptosis. In cells lacking the multidomain proapoptotic Bcl-2 family members Bax and Bak (DKO), hFis1 caused mitochondrial fragmentation but not organelle dysfunction and apoptosis. Similarly, a mutant in the intermembrane region of hFis1-induced fission but not cell death, further dissociating mitochondrial fragmentation from apoptosis induction. Selective correction of the endoplasmic reticulum (ER) defect of DKO cells restored killing by hFis1, indicating that death by hFis1 relies on the ER gateway of apoptosis. Consistently, hFis1 did not directly activate BAX and BAK, but induced Ca(2+)-dependent mitochondrial dysfunction. Thus, hFis1 is a bifunctional protein that independently regulates mitochondrial fragmentation and ER-mediated apoptosis.

Citing Articles

Mitochondrial elongation impairs breast cancer metastasis.

Minarrieta L, Annis M, Audet-Delage Y, Kuasne H, Pacis A, St-Louis C Sci Adv. 2024; 10(45):eadm8212.

PMID: 39504368 PMC: 11540020. DOI: 10.1126/sciadv.adm8212.

A preliminary study of the miRNA restitution effect on CNV-induced miRNA downregulation in CAKUT.

Mitrovic K, Zivotic I, Kolic I, Zakula J, Zivkovic M, Stankovic A BMC Genomics. 2024; 25(1):218.

PMID: 38413914 PMC: 10900603. DOI: 10.1186/s12864-024-10121-8.

Role of Mitochondrial Dynamics in Heart Diseases.

Tokuyama T, Yanagi S Genes (Basel). 2023; 14(10).

PMID: 37895224 PMC: 10606177. DOI: 10.3390/genes14101876.

Mitochondria-Associated Membrane Scaffolding with Endoplasmic Reticulum: A Dynamic Pathway of Developmental Disease.

Saneto R, Perez F Front Mol Biosci. 2022; 9:908721.

PMID: 35775081 PMC: 9237565. DOI: 10.3389/fmolb.2022.908721.

PEX11β and FIS1 cooperate in peroxisome division independently of mitochondrial fission factor.

Schrader T, Carmichael R, Islinger M, Costello J, Hacker C, Bonekamp N J Cell Sci. 2022; 135(13).

PMID: 35678336 PMC: 9377713. DOI: 10.1242/jcs.259924.

References

Pinton P, Ferrari D, Magalhaes P, Schulze-Osthoff K, Di Virgilio F, Pozzan T . Reduced loading of intracellular Ca(2+) stores and downregulation of capacitative Ca(2+) influx in Bcl-2-overexpressing cells. J Cell Biol. 2000; 148(5):857-62. PMC: 2174537. DOI: 10.1083/jcb.148.5.857. View

Karbowski M, Lee Y, Gaume B, Jeong S, Frank S, Nechushtan A . Spatial and temporal association of Bax with mitochondrial fission sites, Drp1, and Mfn2 during apoptosis. J Cell Biol. 2002; 159(6):931-8. PMC: 2173996. DOI: 10.1083/jcb.200209124. View

Santel A, Fuller M . Control of mitochondrial morphology by a human mitofusin. J Cell Sci. 2001; 114(Pt 5):867-74. DOI: 10.1242/jcs.114.5.867. View

Ono T, Isobe K, Nakada K, Hayashi J . Human cells are protected from mitochondrial dysfunction by complementation of DNA products in fused mitochondria. Nat Genet. 2001; 28(3):272-5. DOI: 10.1038/90116. View

Smirnova E, Griparic L, Shurland D, van der Bliek A . Dynamin-related protein Drp1 is required for mitochondrial division in mammalian cells. Mol Biol Cell. 2001; 12(8):2245-56. PMC: 58592. DOI: 10.1091/mbc.12.8.2245. View

Frank S, Gaume B, Bergmann-Leitner E, Leitner W, Robert E, Catez F . The role of dynamin-related protein 1, a mediator of mitochondrial fission, in apoptosis. Dev Cell. 2001; 1(4):515-25. DOI: 10.1016/s1534-5807(01)00055-7. View

Ferri K, Kroemer G . Organelle-specific initiation of cell death pathways. Nat Cell Biol. 2001; 3(11):E255-63. DOI: 10.1038/ncb1101-e255. View

Scorrano L, Ashiya M, Buttle K, Weiler S, Oakes S, Mannella C . A distinct pathway remodels mitochondrial cristae and mobilizes cytochrome c during apoptosis. Dev Cell. 2002; 2(1):55-67. DOI: 10.1016/s1534-5807(01)00116-2. View

Dimmer K, Fritz S, Fuchs F, Messerschmitt M, Weinbach N, Neupert W . Genetic basis of mitochondrial function and morphology in Saccharomyces cerevisiae. Mol Biol Cell. 2002; 13(3):847-53. PMC: 99603. DOI: 10.1091/mbc.01-12-0588. View

10.

Westermann B . Merging mitochondria matters: cellular role and molecular machinery of mitochondrial fusion. EMBO Rep. 2002; 3(6):527-31. PMC: 1084147. DOI: 10.1093/embo-reports/kvf113. View

11.

Nijtmans L, Henderson N, Holt I . Blue Native electrophoresis to study mitochondrial and other protein complexes. Methods. 2002; 26(4):327-34. DOI: 10.1016/S1046-2023(02)00038-5. View

12.

Li C, Fox C, Master S, Bindokas V, Chodosh L, Thompson C . Bcl-X(L) affects Ca(2+) homeostasis by altering expression of inositol 1,4,5-trisphosphate receptors. Proc Natl Acad Sci U S A. 2002; 99(15):9830-5. PMC: 125032. DOI: 10.1073/pnas.152571899. View

13.

Gugliucci A, Ranzato L, Scorrano L, Colonna R, Petronilli V, Cusan C . Mitochondria are direct targets of the lipoxygenase inhibitor MK886. A strategy for cell killing by combined treatment with MK886 and cyclooxygenase inhibitors. J Biol Chem. 2002; 277(35):31789-95. DOI: 10.1074/jbc.M204450200. View

14.

Legros F, Lombes A, Frachon P, Rojo M . Mitochondrial fusion in human cells is efficient, requires the inner membrane potential, and is mediated by mitofusins. Mol Biol Cell. 2002; 13(12):4343-54. PMC: 138638. DOI: 10.1091/mbc.e02-06-0330. View

15.

Chen H, Detmer S, Ewald A, Griffin E, Fraser S, Chan D . Mitofusins Mfn1 and Mfn2 coordinately regulate mitochondrial fusion and are essential for embryonic development. J Cell Biol. 2003; 160(2):189-200. PMC: 2172648. DOI: 10.1083/jcb.200211046. View

16.

Scorrano L, Oakes S, Opferman J, Cheng E, Sorcinelli M, Pozzan T . BAX and BAK regulation of endoplasmic reticulum Ca2+: a control point for apoptosis. Science. 2003; 300(5616):135-9. DOI: 10.1126/science.1081208. View

17.

Scorrano L, Korsmeyer S . Mechanisms of cytochrome c release by proapoptotic BCL-2 family members. Biochem Biophys Res Commun. 2003; 304(3):437-44. DOI: 10.1016/s0006-291x(03)00615-6. View

18.

Santel A, Frank S, Gaume B, Herrler M, Youle R, Fuller M . Mitofusin-1 protein is a generally expressed mediator of mitochondrial fusion in mammalian cells. J Cell Sci. 2003; 116(Pt 13):2763-74. DOI: 10.1242/jcs.00479. View

19.

Yoon Y, Krueger E, Oswald B, McNiven M . The mitochondrial protein hFis1 regulates mitochondrial fission in mammalian cells through an interaction with the dynamin-like protein DLP1. Mol Cell Biol. 2003; 23(15):5409-20. PMC: 165727. DOI: 10.1128/MCB.23.15.5409-5420.2003. View

20.

James D, Parone P, Mattenberger Y, Martinou J . hFis1, a novel component of the mammalian mitochondrial fission machinery. J Biol Chem. 2003; 278(38):36373-9. DOI: 10.1074/jbc.M303758200. View