MITOCHONDRIA THE BIG PICTURE A PRIMER FOR STUDENTS AND RESEARCHERS Thin section view showing evidence of the mitochondrial reticulum Mitochondria labelled with green fluorescent protein expressed ID: 808639
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Slide1
Slides of the figures and other useful images forMITOCHONDRIA, THE BIG PICTURE: A PRIMER FOR STUDENTS AND RESEARCHERS
Slide2Thin section view showing evidence of the mitochondrial reticulum
.
Slide3Mitochondria
labelled
with green fluorescent protein expressed
in the matrix space
.
Slide4Classic picture of mitochondria from a negative stained electron micrograph
Slide5mamamm
matrix
Outer membrane
Inner boundary membrane
Inte
r
membrane
space
Cristae membrane
micos
Intracristal
space
S
chematic showing the mitochondrial compartments
.
Slide6GLUCOSE
G6Pi
PYRUVATE
ACETYL CoA
CO
2
ATP
glycogen
ribose
5-Pi
nucleotides
lactate
amino acids
fatty acids
ketone bodies
sterols
hormones
Glycogen
storage
Gluconeogenesis
Glycolysis
Pentose Phosphate
Pathway
Urea Cycle
Pyruvate
Dehydrogenase
Complex
B
Oxidation
Oxidative
Phosphorylation
Citric Acid
Cycle
triacylglyercol
Fatty Acid Synthes
is
METABOLIC PATHWAYS INVOLVED IN GLUCOSE UTILIZATION
.
Boxed in yellow are mitochondrial pathways
Slide7Short term Cellular Control of Energy Metabolism
G6Pi
pyruvate
acetyl CoA
ATP
Creatine Pi
Fatty Acid
Synthesis
Glycogen
Synthesis
Sterol Synthesis
Triacylglyerol Synthesis
AMP-activated Kinase
creatine
kinase
Acetyl-coA
carboxylase
glycogen
synthase
HMG-
coA
reductase
GPAT
Fatty Acid
Oxidation
Pi
Pi
Pi
Pi
Pi
Slide8Mito/ER contact
Mito biogenesis/OXPHOS/Krebs cycle
Complex I/IV
AKT
SREBP
PGC1alpha
YY1
mTORC1
lipin
Lipid
synthesis
mTORC2
SIRT4
Glutaminolysis
GSK3
Glycolysis
mRNA translation
4E-BP
eiF-4E
TFPAM
SK6
CAD
Nucleotide biosynthesis
PRPS2
ATG13
ULK1
autophagy
mTOR
: the master switch.
Slide9P38MAPK
active
CHOP
ATF2
ERK1/ERK2
(P42/44MAPK)
active
ASK1
inactive
AKT
active
apoptosis
autophagy
RAS
RAF
TRX
TRAFs
Ox Stress
p53
P
P
P
U
JNK
C-Jun
active
P
CHOP
P
mTOR
PI3K
STRESS SIGNALING AS EXEMPLIFIED BY OXIDATIVE STRESS.
Slide10PATHWAY OF FATTY ACID SYNTHESIS
citrate
Mitochondrial
Acetyl CoA
lipoate
elongated saturated
fatty acids
unsaturated
fatty acids
palmitate
malonyl
CoA
ACC1
ACC2
P
i
Pi
pi
malonyl
trnasferase
ACP
(complex I
ATP citrate
lyase
C
C
ytosolic
Acetyl CoA
Fatty acid synthase
N
NADH cytochrome b
reductase
Cytochrome b5
Slide11PATHWAY OF MITOCHONDRIAL FATTY ACID OXIDATION
unsaturated
F.A.
saturated F.A.
acyl CoA DH
’
s
acetyl CoA
short chain
enoyl
-CoA
hydrolase
LCAD
VLCAD
SCAD
SCHAD
ETF.Q
CPT1
CPT2
DECR
ETF
HADHB
MCAD
ACAA2
Slide12Green
fluorescence shows labeled mitochondria, red fluorescence is surface F1F0 reacted with an labeled antibody to the enzymes beta subunit.
Ectopic ATP synthase, shown for HepG2 cells.
Slide13Mitochondrial involvement in apoptosis
.
Proteins in yellow are mitochondrial.
Slide14MCl1
Mcl-1
Ubiq
USP9X
Mule
NOXA
p53
FBW7
Release from MOM
BIM
PUMA
Displaces NOXA
c
-
Myc
Transcriptional
regul
.
Upregulates
NOXA
Promotes de-
ubiq
.
De-
ubiquitinases
Ubiquitin ligase
Apoptosis: regulation of the levels of the anti-apoptotic protein Mcl-1.
Slide15mTOR
p38MAP K
SIRTs
AMPK
PGC-1alpha
PPARs
ERRs
CREB
NRFs
C
YY1
TCA enzymes
Fatty acid oxidation
Mitochondrial biogenesis
ERRs = estrogen receptor related proteins
Control of biogenesis by signaling through PGC1alpha
.
Slide16PGC-1alpha
PPARs
ERRs
NRFs
Fatty acid oxidation
Glucose metabolism
Mitochondrial biogenesis
AMPK
SIRTs
mTOR
p38MAPK
REGULATION OF METABOLISM BY PGC-1ALPHA
GLUT4
ERRs = estrogen receptor
related proteins
Slide17ATP/ADP/AMP
.
Where ATP is required for transport.
METABOLITE
SHUTTLES
Citrate
Malate
Aspartate
Glutamate
Pyruvate
Acetyl CoA
Where membrane potential/proton gradient drives transport
Membrane potential.
PROTEIN IMPORT/ADHERENCE
etc
AND RELEASE.
Nfkappa
B
,
BCl1, PINK1,MCl1
AIF,Cytochrome
c etc.
mtUPR
.
NADH/NAD+
NADPH/NADP+.
ROS/RNS.
Calcium
Mitochondrial retrograde response
Slide18UPR proteins in mitochondria and endoplasmic reticulum.
HSP60
JNK PATHWAY
C-JUN
PKR
e
IF2alpha
PERK
Induces same
genes as
CHOP1
ATF4
Up
reg
of
CHOP1
Mitochondrial UPR (yellow)
ER UPR(blue
)
APOPTOSIS
INHIBITS PROTEIN TRANSLATION
p38MAPK
HSP90
Up
reg
of
H
eme
O
xygenase
P
P
eIF2alpha
ATG13
P
Slide19(
1
:5,000
) Mitochondrial disorders; (e.g., mitochondrial DNA depletion syndromes)
(1:10,000) Fatty acid oxidation disorders
inc.
medium-chain acyl-CoA dehydrogenase deficiency (1:20,000)
(1:15,000) Phenylketonuria
(1:15,000)
Methylmalonicaciduria
.
Methylmalonyl
- CoA
mutase
,
cobalamin
metabolism
(1:40,000)
Aminoacidopathies
(1:50,000)
Peroxisomal disorders; e.g., Zellweger syndrome, neonatal
adrenoleukodystrophy, Refsum's disease)(1:150,000) Maple syrup urine disease (BCOAD)
Inborn Errors of Metabolism and Incidence
Slide20THE GENETICS AND PATHOLOGY OF MITOCHONDRIAL DISEASE
The Journal of Pathology
Volume 241, Issue 2,
pages 236-250, 2 NOV 2016 DOI: 10.1002/path.4809
http://onlinelibrary.wiley.com/doi/10.1002/path.4809/full#path4809-fig-0003
Images of skeletal muscle sections from a patient with a large scale
mtDNA
delection
showing ragged red fibers by
Gomori
and altered levels of
OXPHOS complexes.