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Mitochondria dynamics

Mitochondria not only provide most of the ATP required by the cell, but they are involved in a number of amplificatory signalling cascades that range from Ca2+ signalling to apoptosis. During apoptosis, mitochondria release cytochrome c and other proteins that are required for the competent activation of the effector caspases. This release is associated with a transition towards fragmentation of the tubular mitochondrial network normally found in most eukaryotic cells (Figure 1).

The ultrastructure and the shape changes of the organelle result from the equilibrium between fusion and fission events, controlled by a family of mitochondria-shaping proteins that include dynamin related proteins. These include large GTPases that participate in the tubulation, vesiculation, fission and fusion of biological membranes. They are therefore involved in crucial processes such as endo- and exocytosis.
In the past years we have focused our attention on OPA1, a dynamin related protein of the inner mitochondrial membrane, mutated in dominant optic atrophy. We have shown that OPA1 has multiple, genetically distinguishable functions in mitochondrial fusion and in the control of cristae remodelling and cytochrome c release. While the pro-fusion effect depends on the outer membrane protein of the same family Mitofusin 1 (Cipolat et al, PNAS, 101, 15927-15932, 2004), the remodelling of the cristae depends on the inner mitochondrial membrane rhomboid protease PARL (Cipolat et al., Cell 126, 163- 175, 2006). This is required for the complete processing of OPA1 into a soluble, intermembrane space form that participates together with the membrane bound one in the formation of a high molecular weight oligomer. OPA1-containing oligomers are early targets during remodelling of the cristae in the course of apoptosis (Frezza et al., Cell 126, 177-189, 2006).
Furthermore, we have investigated the role of other mitochondria-shaping proteins of the outer membrane, like Fis1 and the inner membrane, like Letm1 in the relationship between mitochondrial shape and viability. Our results indicate that the main determinant of viability is given by mitochondrial function, rather than shape (Alirol et al., Mol. Biol. Cell 2006; 17:4593-605, and Dimmer et al., Hum Mol. Gen. 2008, 17:201-214).
The main interest of our lab is to investigate the function and the regulation of these mitochondria-shaping proteins. We use an integrated approach of genetics, advanced imaging, biochemistry, physiology and electron tomography to unravel the role of these proteins in cell life and death, especially by generating and analysing mouse models of conditional ablation and overexpression of mitochondria-shaping proteins.

Group's publications

Guidelines for the use and interpretation of assays for monitoring cell death in higher eukaryotes
CELL DEATH AND DIFFERENTIATION
2009 vol. 16(8) pp. 1093-1107
GALLUZZI L. AND AL.

When separation means death: killing through the mitochondria but starting from the endoplasmic reticulum
EMBO JOURNAL
2009 vol. 28(12) pp. 1681-1683
LAMARCA V, SCORRANO L

The SUMO arena goes mitochondrial with MAPL
EMBO REPORTS
2009 vol. 10(7) pp. 694-696
SCORRANO L, LIU D

Opening the doors to cytochrome c: Changes in mitochondrial shape and apoptosis
INTERNATIONAL JOURNAL OF BIOCHEMISTRY AND CELL BIOLOGY
2009 vol. 41(10) pp. 1875-1883
SCORRANO L

Mitofusin-2 regulates mitochondrial and endoplasmic reticulum morphology and tethering: The role of Ras
MITOCHONDRION
2009 vol. 9(3) pp. 222-226
DE BRITO OM, SCORRANO LUCA

Reactive oxygen species are NOXious for neurons
NATURE NEUROSCIENCE
2009 vol. 12(7) pp. 819-820
DEMAUREX N, SCORRANO L

MITOSTATIN, a putative tumor suppressor on chromosome 12q24.1, is downregulated in human bladder and breast cancer.
ONCOGENE : AN INTERNATIONAL JOURNAL
2009 vol. 28(2) pp. 257-269
VECCHIONE A AND AL.

The changing shape of mitochondrial apoptosis
TRENDS IN ENDOCRINOLOGY AND METABOLISM
2009 vol. 20(6) pp. 287-294
WASILEWSKI M, SCORRANO L

Mitofusin-2, A Mitochondria-Shaping Protein with Signaling Roles Beyond Fusion
ANTIOXIDANTS & REDOX SIGNALLING
2008 vol. 10(3) pp. 621-633
MARTINS DE BRITO OLGA, SCORRANO LUCA

High levels of Fis1, a pro-fission mitochondrial protein, trigger autophagy.
BIOCHIMICA ET BIOPHYSICA ACTA : INTERNATIONAL JOURNAL OF BIOCHEMISTRY AND BIOPHYSICS.
2008 vol. 1777(7-8) pp. 860-866
GOMES LC, SCORRANO LUCA

A novel deletion in the GTPase domain of OPA1 causes defects in mitochondrial morphology and distribution, but not in function.
HUMAN MOLECULAR GENETICS
2008 vol. 17(21) pp. 3291-3302
SPINAZZI M AND AL.

LETM1, deleted in Wolf-Hirschhorn syndrome is required for normal mitochondrial morphology and cellular viability.
HUMAN MOLECULAR GENETICS
2008 vol. 17(2) pp. 201-214
DIMMER KS, NAVONI S, CASARIN A, TREVISSON E, ENDELE S, WINTERPACHT A, SALVIATI L, SCORRANO LUCA

Caspase-8 goes cardiolipin: a new platform to provide mitochondria with microdomains of apoptotic signals?
JOURNAL OF CELL BIOLOGY
2008 vol. 183(4) pp. 579-581
SCORRANO LUCA

Measuring mitochondrial shape changes and their consequences on mitochondrial involvement during apoptosis.
METHODS IN MOLECULAR BIOLOGY (CLIFTON, N.J.)
2008 vol. 372 pp. 405-420
FREZZA C, CIPOLAT S, SCORRANO LUCA

Mitofusin 2 tethers endoplasmic reticulum to mitochondria.
NATURE
2008 vol. 456(7222) pp. 605-610
DE BRITO OM, SCORRANO LUCA

Dephosphorylation by calcineurin regulates translocation of Drp1 to mitochondria.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
2008 vol. 105(41) pp. 15803-15808
CEREGHETTI GM, STANGHERLIN A, MARTINS DE BRITO O, CHANG CR, BLACKSTONE C, BERNARDI P, SCORRANO LUCA

A cut short to death: Parl and Opa1 in the regulation of mitochondrial morphology and apoptosis
CELL DEATH AND DIFFERENTIATION
2007 vol. 14(7) pp. 1275-1284
PELLEGRINI L, SCORRANO LUCA

Targeting cell death
CLINICAL PHARMACOLOGY & THERAPEUTICS
2007 vol. 82(4) pp. 370-373
HAUSENLOY DJ, SCORRANO L

Measuring mitochondrial shape changes and their consequences on mitochondrial involvement during apoptosis
METHODS IN MOLECULAR BIOLOGY (CLIFTON, N.J.)
2007 vol. 372 pp. 405-420
FREZZA C, CIPOLAT S, SCORRANO L

Organelle isolation: functional mitochondria from mouse liver, muscle and cultured fibroblasts
NATURE PROTOCOLS
2007 vol. 2(2) pp. 287-295
FREZZA C, CIPOLAT S, SCORRANO LUCA

Multiple functions of mitochondria-shaping proteins
NOVARTIS FOUNDATION SYMPOSIUM
2007 vol. 287 pp. 47-55
SCORRANO LUCA

The relationship between mitochondrial shape and function and the cytoskeleton
BIOCHIMICA ET BIOPHYSICA ACTA : INTERNATIONAL JOURNAL OF BIOCHEMISTRY AND BIOPHYSICS.
2006 vol. 1757(5-6) pp. 692-699
ANESTI V., SCORRANO LUCA

Mitochondrial rhomboid PARL regulates cytochrome c release during apoptosis via OPA1-dependent cristae remodeling
CELL
2006 vol. 126(1) pp. 163-175
CIPOLAT S. ET AL.

OPA1 controls apoptotic cristae remodeling independently from mitochondrial fusion
CELL
2006 vol. 126(1) pp. 177-189
FREZZA C. ET AL.

Laying the foundations of programmed cell death
CELL DEATH AND DIFFERENTIATION
2006 vol. 3(8) pp. 1245-1247
LETAI A, SCORRANO LUCA

To fuse and to protect. A novel role for CED-9 in mitochondrial morphology reveals an ancient function
CELL DEATH AND DIFFERENTIATION
2006 vol. 13(11) pp. 1833-1834
CIPOLAT S, SCORRANO LUCA

Role of endoplasmic reticulum depletion and multidomain proapoptotic BAX and BAK proteins in shaping cell death after hypericin-mediated photodynamic therapy
FASEB JOURNAL
2006 vol. 20(6) pp. 756-758
BUYTAERT E. ET AL.

Orchestration of lymphocyte chemotaxis by mitochondrial dynamics
JOURNAL OF EXPERIMENTAL MEDICINE
2006 vol. 203(13) pp. 2879-2886
CAMPELLO S., BETTELLA M., LACALLE R.A., MANES S., SCORRANO LUCA, VIOLA A.

The mitochondrial fission protein hFis1 requires the endoplasmic reticulum gateway to induce apoptosis
MOLECULAR BIOLOGY OF THE CELL
2006 vol. 17(11) pp. 4593-4605
ALIROL E, JAMES D, HUBER D, MARCHETTO A, VERGANI L, MARTINOU JC, SCORRANO LUCA

The many shapes of mitochondrial death
ONCOGENE : AN INTERNATIONAL JOURNAL
2006 vol. 25(34) pp. 4717-4724
CEREGHETTI GM, SCORRANO LUCA

(De)constructing mitochondria: what for?
PHYSIOLOGY (BETHESDA, MD.)
2006 vol. 21 pp. 233-241
DIMMER KS, SCORRANO LUCA

Proteins that fuse and fragment mitochondria in apoptosis: con-fissing a deadly con-fusion?
JOURNAL OF BIOENERGETICS AND BIOMEMBRANES
2005 vol. 37(3) pp. 165-170
SCORRANO LUCA

Stanley J. Korsmeyer (1950-2005)
JOURNAL OF BIOENERGETICS AND BIOMEMBRANES
2005 vol. 37(3) pp. 109-109
SCORRANO LUCA

Proapoptotic BAX and BAK regulate the type 1 inositol trisphosphate receptor and calcium leak from the endoplasmic reticulum
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
2005 vol. 02(1) pp. 105-110
OAKES S.A., SCORRANO LUCA, OPFERMAN J.T., BASSIK M.C., NISHINO M., POZZAN T., KORSMEYER S.J.

Phosphorylation of BCL-2 regulates ER Ca2+ homeostasis and apoptosis
EMBO JOURNAL
2004 vol. 23(5) pp. 1207-1216
BASSIK M.C., SCORRANO LUCA, OAKES S.A., POZZAN T., KORSMEYER S.J.

Arachidonic acid released by phospholipase A(2) activation triggers Ca(2+)-dependent apoptosis through the mitochondrial pathway
JOURNAL OF BIOLOGICAL CHEMISTRY
2004 vol. 279(24) pp. 25219-25225
PENZO D., PETRONILLI V., ANGELIN A., CUSAN C., COLONNA R., SCORRANO LUCA, PAGANO F., PRATO M., DI LISA F., BERNARDI P.

OPA1 requires mitofusin 1 to promote mitochondrial fusion
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
2004 vol. 101(45) pp. 15927-15932
CIPOLAT S., MARTINS DE BRITO O., DAL ZILIO B., SCORRANO LUCA

Research's domains




DATABASE-RESEARCH	GROUP OF BASIC RESEARCH

Luca SCORRANO	Head of group CV	Research subject	Members of the group


	Links about the group Prof Luca SCORRANO CMU / Dpt PHYM Rue Michel-Servet 1 1211 Genève 4 Suisse Luca.scorrano@unige.ch Tel.: 022 379 52 35 Fax: 022 379 58 02 Comments Pages updated the 17.11.2015		Reseach's subject \| Group's publications \| Research's domains Mitochondria dynamics Mitochondria not only provide most of the ATP required by the cell, but they are involved in a number of amplificatory signalling cascades that range from Ca2+ signalling to apoptosis. During apoptosis, mitochondria release cytochrome c and other proteins that are required for the competent activation of the effector caspases. This release is associated with a transition towards fragmentation of the tubular mitochondrial network normally found in most eukaryotic cells (Figure 1). The ultrastructure and the shape changes of the organelle result from the equilibrium between fusion and fission events, controlled by a family of mitochondria-shaping proteins that include dynamin related proteins. These include large GTPases that participate in the tubulation, vesiculation, fission and fusion of biological membranes. They are therefore involved in crucial processes such as endo- and exocytosis. In the past years we have focused our attention on OPA1, a dynamin related protein of the inner mitochondrial membrane, mutated in dominant optic atrophy. We have shown that OPA1 has multiple, genetically distinguishable functions in mitochondrial fusion and in the control of cristae remodelling and cytochrome c release. While the pro-fusion effect depends on the outer membrane protein of the same family Mitofusin 1 (Cipolat et al, PNAS, 101, 15927-15932, 2004), the remodelling of the cristae depends on the inner mitochondrial membrane rhomboid protease PARL (Cipolat et al., Cell 126, 163- 175, 2006). This is required for the complete processing of OPA1 into a soluble, intermembrane space form that participates together with the membrane bound one in the formation of a high molecular weight oligomer. OPA1-containing oligomers are early targets during remodelling of the cristae in the course of apoptosis (Frezza et al., Cell 126, 177-189, 2006). Furthermore, we have investigated the role of other mitochondria-shaping proteins of the outer membrane, like Fis1 and the inner membrane, like Letm1 in the relationship between mitochondrial shape and viability. Our results indicate that the main determinant of viability is given by mitochondrial function, rather than shape (Alirol et al., Mol. Biol. Cell 2006; 17:4593-605, and Dimmer et al., Hum Mol. Gen. 2008, 17:201-214). The main interest of our lab is to investigate the function and the regulation of these mitochondria-shaping proteins. We use an integrated approach of genetics, advanced imaging, biochemistry, physiology and electron tomography to unravel the role of these proteins in cell life and death, especially by generating and analysing mouse models of conditional ablation and overexpression of mitochondria-shaping proteins. Group's publications Guidelines for the use and interpretation of assays for monitoring cell death in higher eukaryotes CELL DEATH AND DIFFERENTIATION 2009 vol. 16(8) pp. 1093-1107 GALLUZZI L. AND AL. When separation means death: killing through the mitochondria but starting from the endoplasmic reticulum EMBO JOURNAL 2009 vol. 28(12) pp. 1681-1683 LAMARCA V, SCORRANO L The SUMO arena goes mitochondrial with MAPL EMBO REPORTS 2009 vol. 10(7) pp. 694-696 SCORRANO L, LIU D Opening the doors to cytochrome c: Changes in mitochondrial shape and apoptosis INTERNATIONAL JOURNAL OF BIOCHEMISTRY AND CELL BIOLOGY 2009 vol. 41(10) pp. 1875-1883 SCORRANO L Mitofusin-2 regulates mitochondrial and endoplasmic reticulum morphology and tethering: The role of Ras MITOCHONDRION 2009 vol. 9(3) pp. 222-226 DE BRITO OM, SCORRANO LUCA Reactive oxygen species are NOXious for neurons NATURE NEUROSCIENCE 2009 vol. 12(7) pp. 819-820 DEMAUREX N, SCORRANO L MITOSTATIN, a putative tumor suppressor on chromosome 12q24.1, is downregulated in human bladder and breast cancer. ONCOGENE : AN INTERNATIONAL JOURNAL 2009 vol. 28(2) pp. 257-269 VECCHIONE A AND AL. The changing shape of mitochondrial apoptosis TRENDS IN ENDOCRINOLOGY AND METABOLISM 2009 vol. 20(6) pp. 287-294 WASILEWSKI M, SCORRANO L Mitofusin-2, A Mitochondria-Shaping Protein with Signaling Roles Beyond Fusion ANTIOXIDANTS & REDOX SIGNALLING 2008 vol. 10(3) pp. 621-633 MARTINS DE BRITO OLGA, SCORRANO LUCA High levels of Fis1, a pro-fission mitochondrial protein, trigger autophagy. BIOCHIMICA ET BIOPHYSICA ACTA : INTERNATIONAL JOURNAL OF BIOCHEMISTRY AND BIOPHYSICS. 2008 vol. 1777(7-8) pp. 860-866 GOMES LC, SCORRANO LUCA A novel deletion in the GTPase domain of OPA1 causes defects in mitochondrial morphology and distribution, but not in function. HUMAN MOLECULAR GENETICS 2008 vol. 17(21) pp. 3291-3302 SPINAZZI M AND AL. LETM1, deleted in Wolf-Hirschhorn syndrome is required for normal mitochondrial morphology and cellular viability. HUMAN MOLECULAR GENETICS 2008 vol. 17(2) pp. 201-214 DIMMER KS, NAVONI S, CASARIN A, TREVISSON E, ENDELE S, WINTERPACHT A, SALVIATI L, SCORRANO LUCA Caspase-8 goes cardiolipin: a new platform to provide mitochondria with microdomains of apoptotic signals? JOURNAL OF CELL BIOLOGY 2008 vol. 183(4) pp. 579-581 SCORRANO LUCA Measuring mitochondrial shape changes and their consequences on mitochondrial involvement during apoptosis. METHODS IN MOLECULAR BIOLOGY (CLIFTON, N.J.) 2008 vol. 372 pp. 405-420 FREZZA C, CIPOLAT S, SCORRANO LUCA Mitofusin 2 tethers endoplasmic reticulum to mitochondria. NATURE 2008 vol. 456(7222) pp. 605-610 DE BRITO OM, SCORRANO LUCA Dephosphorylation by calcineurin regulates translocation of Drp1 to mitochondria. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2008 vol. 105(41) pp. 15803-15808 CEREGHETTI GM, STANGHERLIN A, MARTINS DE BRITO O, CHANG CR, BLACKSTONE C, BERNARDI P, SCORRANO LUCA A cut short to death: Parl and Opa1 in the regulation of mitochondrial morphology and apoptosis CELL DEATH AND DIFFERENTIATION 2007 vol. 14(7) pp. 1275-1284 PELLEGRINI L, SCORRANO LUCA Targeting cell death CLINICAL PHARMACOLOGY & THERAPEUTICS 2007 vol. 82(4) pp. 370-373 HAUSENLOY DJ, SCORRANO L Measuring mitochondrial shape changes and their consequences on mitochondrial involvement during apoptosis METHODS IN MOLECULAR BIOLOGY (CLIFTON, N.J.) 2007 vol. 372 pp. 405-420 FREZZA C, CIPOLAT S, SCORRANO L Organelle isolation: functional mitochondria from mouse liver, muscle and cultured fibroblasts NATURE PROTOCOLS 2007 vol. 2(2) pp. 287-295 FREZZA C, CIPOLAT S, SCORRANO LUCA Multiple functions of mitochondria-shaping proteins NOVARTIS FOUNDATION SYMPOSIUM 2007 vol. 287 pp. 47-55 SCORRANO LUCA The relationship between mitochondrial shape and function and the cytoskeleton BIOCHIMICA ET BIOPHYSICA ACTA : INTERNATIONAL JOURNAL OF BIOCHEMISTRY AND BIOPHYSICS. 2006 vol. 1757(5-6) pp. 692-699 ANESTI V., SCORRANO LUCA Mitochondrial rhomboid PARL regulates cytochrome c release during apoptosis via OPA1-dependent cristae remodeling CELL 2006 vol. 126(1) pp. 163-175 CIPOLAT S. ET AL. OPA1 controls apoptotic cristae remodeling independently from mitochondrial fusion CELL 2006 vol. 126(1) pp. 177-189 FREZZA C. ET AL. Laying the foundations of programmed cell death CELL DEATH AND DIFFERENTIATION 2006 vol. 3(8) pp. 1245-1247 LETAI A, SCORRANO LUCA To fuse and to protect. A novel role for CED-9 in mitochondrial morphology reveals an ancient function CELL DEATH AND DIFFERENTIATION 2006 vol. 13(11) pp. 1833-1834 CIPOLAT S, SCORRANO LUCA Role of endoplasmic reticulum depletion and multidomain proapoptotic BAX and BAK proteins in shaping cell death after hypericin-mediated photodynamic therapy FASEB JOURNAL 2006 vol. 20(6) pp. 756-758 BUYTAERT E. ET AL. Orchestration of lymphocyte chemotaxis by mitochondrial dynamics JOURNAL OF EXPERIMENTAL MEDICINE 2006 vol. 203(13) pp. 2879-2886 CAMPELLO S., BETTELLA M., LACALLE R.A., MANES S., SCORRANO LUCA, VIOLA A. The mitochondrial fission protein hFis1 requires the endoplasmic reticulum gateway to induce apoptosis MOLECULAR BIOLOGY OF THE CELL 2006 vol. 17(11) pp. 4593-4605 ALIROL E, JAMES D, HUBER D, MARCHETTO A, VERGANI L, MARTINOU JC, SCORRANO LUCA The many shapes of mitochondrial death ONCOGENE : AN INTERNATIONAL JOURNAL 2006 vol. 25(34) pp. 4717-4724 CEREGHETTI GM, SCORRANO LUCA (De)constructing mitochondria: what for? PHYSIOLOGY (BETHESDA, MD.) 2006 vol. 21 pp. 233-241 DIMMER KS, SCORRANO LUCA Proteins that fuse and fragment mitochondria in apoptosis: con-fissing a deadly con-fusion? JOURNAL OF BIOENERGETICS AND BIOMEMBRANES 2005 vol. 37(3) pp. 165-170 SCORRANO LUCA Stanley J. Korsmeyer (1950-2005) JOURNAL OF BIOENERGETICS AND BIOMEMBRANES 2005 vol. 37(3) pp. 109-109 SCORRANO LUCA Proapoptotic BAX and BAK regulate the type 1 inositol trisphosphate receptor and calcium leak from the endoplasmic reticulum PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2005 vol. 02(1) pp. 105-110 OAKES S.A., SCORRANO LUCA, OPFERMAN J.T., BASSIK M.C., NISHINO M., POZZAN T., KORSMEYER S.J. Phosphorylation of BCL-2 regulates ER Ca2+ homeostasis and apoptosis EMBO JOURNAL 2004 vol. 23(5) pp. 1207-1216 BASSIK M.C., SCORRANO LUCA, OAKES S.A., POZZAN T., KORSMEYER S.J. Arachidonic acid released by phospholipase A(2) activation triggers Ca(2+)-dependent apoptosis through the mitochondrial pathway JOURNAL OF BIOLOGICAL CHEMISTRY 2004 vol. 279(24) pp. 25219-25225 PENZO D., PETRONILLI V., ANGELIN A., CUSAN C., COLONNA R., SCORRANO LUCA, PAGANO F., PRATO M., DI LISA F., BERNARDI P. OPA1 requires mitofusin 1 to promote mitochondrial fusion PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2004 vol. 101(45) pp. 15927-15932 CIPOLAT S., MARTINS DE BRITO O., DAL ZILIO B., SCORRANO LUCA Research's domains