inactive zymogens

IL-1

point
of
no
return?

mature protease
 CED-4
(heterodimer) WD40

Apaf-1

CARD

Sensors

Guardians

t(14:18)
Effectors
Do Apaf-1-like adaptors and Bcl-2-like proteins
have non-apoptotic functions?
 Non-apoptotic functions
Bcl-2 superfamily

•  Localization, in part, to mitochondria

–  implicated in various aspects of mitochondrial function
…conclusive
Bad BH3
Also:
Bik
evidence for their
Bim BH3
TM
domain
Hrk
Puma EGL-1 non-apoptotic
functions are still
Noxa
Bid BH3 Bmf

Also: missing
Bcl-2 BH4 BH3 BH1 BH2
TM
Bcl-w
CED-9
domain

Mcl-1
Bcl-xL BH4 BH3 BH1 BH2
TM
domain Bcl-B
Bcl-2A1

Bax BH3 BH1 BH2

TM
domain Also:
Bok
Bak BH3 BH1 BH2
TM
domain

BI-FUNCTIONAL PROTEINS
 Bax and mitochondrial dynamics

•  Martinou, Youle and co-workers

–  expression of Bax causes a change in the morphology of mitochondria

Fission

Fusion
 Bax and mitochondrial dynamics

•  Martinou, Youle and co-workers

–  expression of Bax causes a change in the morphology of mitochondria
–  fragmentation of mitochondrial network
–  mediated by Drp-1 Bax
Drp-1

•  dynamin-related GTPase Fission

Karbowski, M. et al. (2002). Spatial and temporal association of Bax with mitochondrial
fission sites, Drp1, and Mfn2 during apoptosis. J Cell Biol, 159(6), 931-938.
http://dx.doi.org/10.1083/jcb.200209124
 Bax and mitochondrial dynamics

•  Martinou, Youle and co-workers

–  expression of Bax causes a change in the morphology of mitochondria
–  fragmentation of mitochondrial network
–  mediated by Drp-1 Bax
Drp-1
dominant negative
construct
•  dynamin-related GTPase Fission

This suggested that

Bax-induced mitochondrial
fragmentation contributes to
apoptotic
the apoptotic process process
Karbowski, M. et al. (2002). Spatial and temporal association of Bax with mitochondrial
fission sites, Drp1, and Mfn2 during apoptosis. J Cell Biol, 159(6), 931-938.
slowed
http://dx.doi.org/10.1083/jcb.200209124
 Bax and mitochondrial dynamics

Mitochondrial fragmentation might

promote cytochrome c release!
 Mitochondrial fragmentation
in C. elegans
apoptosis blocked
Drp-1 in some of the
•  During C. elegans development: dominant negative 131 cells
(fission blocked)
egl-1 detected

Drp-1
induction of
ectopic apoptosis
overexpression
(hyperfission)

fragmentation detected

EGL-1
20 minutes +
Jagasia, R. et al. (2005). DRP-1-mediated mitochondrial fragmentation during EGL-1- CED-9
( )
induced cell death in C. elegans. Nature, 433(7027), 754-760. required for
http://dx.doi.org/10.1038/nature03316 fragmentation
 Mitochondrial fragmentation
in C. elegans

EGL-1
CED-9

Bax effector-like

mammals C. elegans
 Non-apoptotic functions
Bcl-2 superfamily

•  Expression of ced-9 in healthy cells of C. elegans

–  induces mitochondrial fusion Fission
–  dependent on FZO-1 and EAT-3
•  dynamin-related GTPases

EAT-3
Fusion

FZO-1
ced-9
expression
 Non-apoptotic functions
Bcl-2 superfamily
Is the ability of Bcl-2-like proteins to induce mitochondrial fusion conserved?
•  2006 – Youle and co-workers
–  Bax and Bak are required for mitochondrial fusion
–  they activate assembly of mitofusin Bcl-xL
•  another dynamin-related GTPase

Mcl-1
 
double knock-out mouse
(no Bax or Bak)

Karbowski, M. et al. (2006). Role of Bax and Bak in mitochondrial morphogenesis.

Nature, 443(7112), 658-662.
http://dx.doi.org/10.1038/nature05111
 Fission

Bcl-2-like
proteins

Fusion

ATP

ATP

What is the physiological role of

mitochondrial dynamics in the first place?
 Fission

Bcl-2-like
proteins

Fusion

Is this the physiological,

non-apoptotic function of
Bcl-2-like proteins?

Ca2+
 Alavian, K.N. et al. (2011). Bcl-xL regulates metabolic efficiency of neurons through interaction
with the mitochondrial F1FO ATP synthase. Nat Cell Biol, 13(10), 1224-1233.
http://dx.doi.org/10.1038/ncb2330

outer membrane
Effectors
inner membrane

matrix

Bcl-
xL

Bcl-xL
 Parciavalle, R.M. et al. (2012). Anti-apoptotic MCL-1 localizes to the mitochondrial matrix
and couples mitochondrial fusion to respiration. Nat Cell Biol, 14(6), 575-583.
http://dx.doi.org/10.1038/ncb2488

Effectors

Mcl-1

Mcl- Bcl-
1 xL

Bcl-xL
 Fission

Bcl-2-like
proteins

Fusion

Is this the physiological,

non-apoptotic function of
Bcl-2-like proteins?

a recent review by Marie Hardwick…

Hardwick, J.M. et al. (2012). Multipolar functions of BCL-2 proteins link energetics to
apoptosis. Treands Cell Biol, 22(6), 318-328.
http://dx.doi.org/10.1016/j.tcb.2012.03.005