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Mitochondrial dynamics, mitophagy, and autophagy

Mitochondrial fusion and fission pathways
Mitochondrial import protein pathway

iΔΨm, (OXPHOSh) (Cell differentiationi)

Ca2+

Fusion

++++N

Internal signal sequence

β-barrel outer membrane precursors

Opa1

SH SH

ER

Mfn1/2

SH SH

GTP
GTP

GTP
GTP

GTP

C
Inner membrane and

Matrix carrier precursors

(N-terminal presequences)

Outer membrane fusion

22
70

GTP

35
37
20

6
5

Sam complex

Opa1

Tom complex
Cytosol

Outer membrane

Sam50
7

DRP1

Inner membrane fusion
Fis1

Mdm10
Tim8-Tim13

Bax/Bak apoptosis

Tom40

HR2 regions

S-S S-S

Tim9-Tim10
Erv1

95 A

Inner mitochondrial space

54

S-S

Reorganization sequestration

Mia40

Fission

21
50

18
18

Translocation to meet ATP needs
Depolarization

Tim22

iΔΨm

  • KREBS Cycle
  • NADH FADH2

Tim23
44

Oxa1

17

Tim 22 complex

  • Mba1
  • Mdm

38

Mia

I
ATP
H+

H+ H+
II III IV H+

17

ADP - Pi

+++

16

Oxa

mtHsp70

ATP

+++

MPP

Mge1

  • Healthy mitochondrion
  • Mitophagy

Matrix
Tim 23 complex

  • Mitophagy pathway
  • Autophagy pathway

Lysosomal hydroiase

Lysosome

Hypoxia, Nutrient/Growth Rapamycin Starvation condition factor deprivation

Ubiquitin
Cytosol

Parkin

Lamp

Damaged mitochondrion

Parkin

Stress

Parkin
Mfn1

PINK1

iΔΨm

Parkin VDAC1
MARF

PINK1
PINK1

mTOR
AMPK

Parkin
Mfn2

PINK1
PINK1

Autophagolyosome

  • Phagophore
  • Autophagosome

PARL

LC3-II

Parkin FIS1

  • PINK1-L
  • PINK1-S

P

  • ATG13
  • ULK

LC3-II

Membrane

FIP200

  • PINK1
  • PINK1

PINK1

MIRO2
Parkin

P

Bak Parkin

PINK1

MIRO1 Parkin

Cytoplasmic macromolecule

  • Cytosol
  • proLC3

Atg4B

LC3-II

Organelle

  • Atg7/LC3-I
  • Atg5/Atg12/Atg16

PE

Atg9
Atg18
Atg2

Atg5/Atg12/Atg16

LC3-II

  • LC3-I
  • Atg3/LC3-I
  • LC3-II

LC3-II
LC3-II

Mitochondrion

Autophagosome formation

  • Autophagosome
  • Autolysosome

P13K III Beclin1
Atg16L
Atg12
Atg5

PE

LC3-II p150

Atg14

Fusion

LC3-II
LC3-II

  • Atg10
  • Atg16L

Atg5
Atg12

Phosphatidyl-ethanolamine deactivation

p62

Atg5
Atg12

LC3-II

Cathepsin

HDAC6

Bcl-2
Atg10

Mfn1

Cathepsin

LC3-I
Atg3

MARF
Mfn2

Wortmannin
3-Methyladenine

  • Atg7
  • Atg5

p62

Atg10
Atg12

VDAC1

Atg3
LC3-I
Atg7
Atg7 Atg10

Lipase

Cathepsin

Lipase

Lysosome

Atg7

  • Atg12
  • Atg7

LC3-I

Atg7

  • Atg12
  • Atg4

LC3

To find out more, please visit

www.abcam.com/mitochondrialdynamics

Copyright © 2018 Abcam, All rights reserved. This poster was made in collaboration with Michelangelo Campanella, Department of Comprarative Biomedical Sciences, The Royal Veterinary College, University of London.

Mitochondrial dynamics, mitophagy, and autophagy

Mitochondrial fusion and fission pathways
Mitochondrial import protein pathway

iΔΨm, (OXPHOSh) (Cell differentiationi)

Ca2+

Fusion

++++N

Internal signal sequence

β-barrel outer membrane precursors

Opa1

SH SH

ER

Mfn1/2

SH SH

GTP GTP

GTP GTP

GTP

C
Inner membrane and

Matrix carrier precursors

(N-terminal presequences)

Outer membrane fusion

  • 22
  • 70

GTP

35
37
20

6
5

Sam complex

Opa1

Tom complex
Cytosol

Outer membrane

Sam50
7

DRP1

Inner membrane fusion
Fis1

Mdm10
Tim8-Tim13

Bax/Bak apoptosis

Tom40

HR2 regions

S-S S-S

Tim9-Tim10
Erv1

95 A

Inner mitochondrial space

54

S-S

Reorganization sequestration

Mia40

Fission

21
50

18
18

Translocation to meet ATP needs
Depolarization

Tim22

iΔΨm

  • KREBS Cycle
  • NADH FADH2

Tim23
44

Oxa1

17

Tim 22 complex

  • Mba1
  • Mdm

38

Mia

I
ATP
H+

H+ H+
II III IV H+

17

ADP - Pi

+++

16

Oxa

mtHsp70

ATP

+++

MPP

Mge1

  • Healthy mitochondrion
  • Mitophagy

  • Matrix
  • Tim 23 complex

  • Mitophagy pathway
  • Autophagy pathway

Lysosomal hydroiase

Lysosome

Hypoxia, Nutrient/Growth Rapamycin Starvation condition factor deprivation

Ubiquitin
Cytosol

Parkin

Lamp

Damaged mitochondrion

Parkin

Stress

Parkin Mfn1

PINK1

iΔΨm

Parkin VDAC1
MARF

  • PINK1
  • PINK1

mTOR
AMPK

Parkin Mfn2

PINK1
PINK1

Autophagolyosome

  • Phagophore
  • Autophagosome

PARL

LC3-II

Parkin FIS1

  • PINK1-L
  • PINK1-S

P

  • ATG13
  • ULK

LC3-II

Membrane

FIP200

  • PINK1
  • PINK1

PINK1

MIRO2 Parkin

P

Bak Parkin

PINK1

MIRO1 Parkin

Cytoplasmic macromolecule

  • Cytosol
  • proLC3

Atg4B

LC3-II

Organelle

  • Atg7/LC3-I
  • Atg5/Atg12/Atg16

PE

Atg9

  • Atg18
  • Atg2

Atg5/Atg12/Atg16

LC3-II

  • LC3-I
  • Atg3/LC3-I
  • LC3-II

LC3-II
LC3-II

Mitochondrion

Autophagosome formation

  • Autophagosome
  • Autolysosome

P13K III Beclin1
Atg16L Atg12 Atg5

PE

LC3-II p150

Atg14

Fusion

LC3-II
LC3-II

  • Atg10
  • Atg16L

Atg5 Atg12

Phosphatidyl-ethanolamine deactivation

p62

Atg5 Atg12

LC3-II

Cathepsin

HDAC6

Bcl-2

Mfn1

Atg10

Cathepsin

LC3-I Atg3

MARF
Mfn2

Wortmannin
3-Methyladenine

  • Atg7
  • Atg5

p62

Atg10 Atg12

VDAC1

Atg3
LC3-I Atg7
Atg7 Atg10

Lipase

Cathepsin

Lipase

Lysosome

Atg7

  • Atg12
  • Atg7

LC3-I

Atg7

  • Atg12
  • Atg4

LC3

To find out more, please visit

www.abcam.com/mitochondrialdynamics

Copyright © 2018 Abcam, All rights reserved. This poster was made in collaboration with Michelangelo Campanella, Department of Comprarative Biomedical Sciences, The Royal Veterinary College, University of London.

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  • Mitochondria-Associated Membranes (Mams) Are Involved in Bax Mitochondrial Localization and Cytochrome C Release

    Mitochondria-Associated Membranes (Mams) Are Involved in Bax Mitochondrial Localization and Cytochrome C Release

    bioRxiv preprint doi: https://doi.org/10.1101/443606; this version posted October 15, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Mitochondria-Associated Membranes (MAMs) are involved in Bax mitochondrial localization and cytochrome c release Alexandre Légiot, Claire Céré, Thibaud Dupoiron, Mohamed Kaabouni, Stéphen Manon1 Institut de Biochimie et de Génétique Cellulaires, UMR 5095 CNRS & Université de Bordeaux, Campus Carreire, CS61390, 1 Rue Camille Saint-Saëns, 33077 Bordeaux, France 1: correspondence to [email protected] Abstract The distribution of the pro-apoptotic protein Bax in the outer mitochondrial membrane (OMM) is a central point of regulation of apoptosis. It is now widely recognized that parts of the endoplasmic reticulum (ER) are closely associated to the OMM, and are actively involved in different signalling processes. We adressed a possible role of these domains, called Mitochondria-Associated Membranes (MAMs) in Bax localization and fonction, by expressing the human protein in a yeast mutant deleted of MDM34, a ERMES component (ER-Mitochondria Encounter Structure). By affecting MAMs stability, the deletion of MDM34 altered Bax mitochondrial localization, and decreased its capacity to release cytochrome c. Furthermore, the deletion of MDM34 decreased the size of an uncompletely released, MAMs-associated pool of cytochrome c. Introduction Apoptosis, the major programmed cell death pathway in animals, plays a central role during development, and along the whole life, by mediating the elimination of dispensable or potentially dangerous cells. Apoptosis is also involved in the response of cells to toxic molecules, such as anti- tumoral drugs.
  • The Pathways of Mitophagy for Quality Control and Clearance of Mitochondria

    The Pathways of Mitophagy for Quality Control and Clearance of Mitochondria

    Cell Death and Differentiation (2013) 20, 31–42 & 2013 Macmillan Publishers Limited All rights reserved 1350-9047/13 www.nature.com/cdd Review The pathways of mitophagy for quality control and clearance of mitochondria G Ashrafi1,3 and TL Schwarz*,1,2 Selective autophagy of mitochondria, known as mitophagy, is an important mitochondrial quality control mechanism that eliminates damaged mitochondria. Mitophagy also mediates removal of mitochondria from developing erythrocytes, and contributes to maternal inheritance of mitochondrial DNA through the elimination of sperm-derived mitochondria. Recent studies have identified specific regulators of mitophagy that ensure selective sequestration of mitochondria as cargo. In yeast, the mitochondrial outer membrane protein autophagy-related gene 32 (ATG32) recruits the autophagic machinery to mitochondria, while mammalian Nix is required for degradation of erythrocyte mitochondria. The elimination of damaged mitochondria in mammals is mediated by a pathway comprised of PTEN-induced putative protein kinase 1 (PINK1) and the E3 ubiquitin ligase Parkin. PINK1 and Parkin accumulate on damaged mitochondria, promote their segregation from the mitochondrial network, and target these organelles for autophagic degradation in a process that requires Parkin-dependent ubiquitination of mitochondrial proteins. Here we will review recent advances in our understanding of the different pathways of mitophagy. In addition, we will discuss the relevance of these pathways in neurons where defects in mitophagy have been