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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
in the matrix space.
Classic picture of mitochondria from a negative stained electron
micrograph
Schematic showing the mitochondrial compartments.
Outer membrane
Inner boundary membrane
matrix
Intermembrane
space
mamamm
Cristae membrane
Intracristal space
micos
GLUCOSE
Glycogen
storage
ribose
5-Pi
G6Pi
glycogen
nucleotides
Pentose Phosphate
Pathway
Glycolysis
Gluconeogenesis
Urea Cycle
lactate
PYRUVATE
Pyruvate
Dehydrogenase
Complex
hormones
sterols
ACETYL CoA
Oxidative
Phosphorylation
Boxed in yellow
are mitochondrial
pathways
Citric Acid
Cycle
CO2 ATP
amino acids
B Oxidation
fatty acids
Fatty Acid Synthesis
ketone bodies
triacylglyercol
METABOLIC PATHWAYS INVOLVED IN GLUCOSE UTILIZATION.
Short term Cellular Control of Energy Metabolism
AMP-activated Kinase
Glycogen
Synthesis
Sterol
Synthesis
Pi
glycogen
synthase
Pi
HMG-coA
reductase
G6Pi
Pi
creatine
kinase
pyruvate
acetyl CoA
Pi
Acetyl-coA
carboxylase
Pi
GPAT
Triacylglyerol
Synthesis
Creatine Pi
ATP
Fatty Acid
Oxidation
Fatty Acid
Synthesis
mTOR: the master switch.
mTORC2
mTORC1
lipin
Lipid
synthesis
ATG13
AKT
SREBP
GSK3
Glycolysis
Mito/ER
contact
4E-BP
SIRT4
SK6
Glutaminolysis
Mito
biogenesis/
OXPHOS/Kr
ebs cycle
ULK
1
PGC1
alph
a
TFPAM
autophagy
eiF-4E
YY1
mRNA
translation
PRPS2
CAD
Complex I/IV
Nucleotide biosynthesis
STRESS SIGNALING AS EXEMPLIFIED BY OXIDATIVE STRESS.
Ox Stress
RAS
TRAFs
PI3K
TRX
P
RAF
P
U
ASK1
JNK
inactive
P
C-Jun
active
P
ERK1/ERK2
(P42/44MAPK)
AKT
P
active
active
P38MAPK
active
p53
mTOR
ATF2
autophagy
CHOP
apoptosis
CHOP
PATHWAY OF FATTY ACID SYNTHESIS
Pi
Mitochondrial
Acetyl CoA
ACP
(complex I
citrate
CCytosolic
Acetyl CoA
ATP citrate
lyase
P
i
ACC2
ACC1
p
i
malonyl
CoA
Fatty acid
synthase
malonyl
trnasferase
palmitate
Cytochrome b5
lipoate
elongated
saturated
fatty acids
NNADH
cytochrome b
reductase
unsaturated
fatty acids
PATHWAY OF MITOCHONDRIAL FATTY ACID OXIDATION
DECR
CPT2
CPT1
LCAD
VLCAD
HADH
B
unsaturated
F.A.
saturated
F.A.
MCAD
SCAD
short chain
enoyl-CoA
hydrolase
SCHA
D
ACAA2
acetyl CoA
ETF
acyl CoA
DH’s
ETF.Q
Ectopic ATP synthase, shown for HepG2 cells.
Green fluorescence shows
labeled mitochondria, red
fluorescence is surface F1F0
reacted with an labeled
antibody to the enzymes
beta subunit.
Mitochondrial involvement in apoptosis.
FasL
Fas
FADD
ER stress
CELL DEATH
CLEAVED
PARP
Caspase 8
procaspase3
Bid
Puma
p38MAPK
bak
Bim
Bcl-xL
caspase7
MCl1
mitochondria
BCl2
caspase9
AIF
p53
Cleaved
Casp3
Bad
Noxa
bax
cytc
nucleus
Apaf-1
DNA damage
Proteins in yellow are mitochondrial.
Aptosome
Apoptosis: regulation of the levels of the anti-apoptotic
protein Mcl-1.
Ubiquitin ligase
Transcriptional regul.
c-Myc
MCl1
Ubiq
Release from
MOM
Displaces
NOXA
Mcl-1
NOXA
BIM
PUMA
FBW7
De-ubiquitinases
Promotes de-ubiq.
p53
Upregulates
NOXA
USP9X
Mule
Control of biogenesis by signaling through PGC1alpha.
SIRTs
AMPK
mTOR
p38MAP K
PGC-1alpha
PPARs
TCA enzymes
ERRs
Fatty acid oxidation
ERRs = estrogen receptor related proteins
CREB
NRFs
Mitochondrial
biogenesis
CYY1
REGULATION OF METABOLISM BY PGC-1ALPHA
SIRTs
mTOR
AMPK
p38MAPK
PGC-1alpha
PPARs
Fatty acid oxidation
ERRs = estrogen receptor related proteins
ERRs
GLUT4
Glucose metabolism
NRFs
Mitochondrial
biogenesis
Mitochondrial retrograde response
ATP/ADP/AMP.
mtUPR
.
Where ATP is required for
transport.
NADH/NAD+
NADPH/NADP+.
METABOLITE
SHUTTLES
Citrate
Malate
Aspartate
Glutamate
Pyruvate
Acetyl CoA
Where membrane
potential/proton
gradient drives transport
ROS/RNS.
Calcium
Membrane
potential.
PROTEIN IMPORT/ADHERENCE etc
AND RELEASE. Nfkappa B, BCl1,
PINK1,MCl1
AIF,Cytochrome c etc.
UPR proteins in mitochondria and endoplasmic reticulum.
JNK
PATHWAY
HSP60
P
p38MAPK
C-JUN
Induces same
genes as CHOP1
Up reg of
Heme Oxygenase
PKR
P
eIF2alpha
HSP90
PERK
eIF2alpha
ATF4
ER UPR(blue)
Mitochondrial UPR (yellow)
INHIBITS PROTEIN
TRANSLATION
Up reg of
CHOP1
P
ATG13
APOPTOSIS
Inborn Errors of Metabolism and Incidence
(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)
THE GENETICS AND PATHOLOGY OF MITOCHONDRIAL DISEASE
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.
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