Function

Peroxisome dynamics in health and disease

Eukaryoc cells contain disnct membrane-bound organelles, which compartmentalise cellular proteins to full a variety of vital
funcons. Many organelles such as peroxisomes have long been regarded as isolated and stac enes, but we provided evidence
that they are highly dynamic. Their complex behaviour determines organelle number, distribuon, inheritance, turnover, metabolic
cooperaon and organelle interacon. Our discovery and molecular characterisaon of peroxisome morphology proteins regulang
these processes has now supported the idencaon, diagnosis and understanding of novel disorders with defects in organelle
dynamics.
Novel disorders with defects in peroxisome dynamics

Gene

Function

Mutation

Clinical features

Organelle morphology

Reference

DNM1L
DLP1
mitochondrial and peroxisomal
membrane ssion
c.1184C>A
A395D

Heterozygous

Dominant-negative
Oligomerisation defect

Microcephaly, abnormal brain
development, optic atrophy, hypoplasia;
lactic acidosis, slightly elevated VLCFA
levels

Elongated and constricted
peroxisomes; elongated
mitochondria with uneven
diameter

Waterham et al.
2007
MFF

recruitment of DLP1 to
mitochondria and peroxisomes

c.190C>T

Q64X

Homozygous

nonsense mutation

Truncated protein lacking
TMD

Developmental delay, abnormal intensity
on brain MRI of the globus pallidus,
motor and speech decits, mild
hypertonia, borderline microcephaly,
pale optic discs

Elongated peroxisomes
and mitochondria

Shamseldin et al.
2012

GDAP1

GST-transferase; involved in
mitochondrial and peroxisomal
division


Heteroallelic

Charcot-Marie-Tooth neuropathy; -

Hoarse voice and vocal cord paresis,
onset at childhood with weakness and
hand wasting leading to disability at the
end of the rst decade, sensory nerve
action potential decreased or absent

Inability to induce
mitochondrial and
peroxisomal fragmentation*

Cuesta et al. 2002

Niemann et al. 2005

Huber et al. 2013

Frameshift
mutation
c.863insA

T288fs290X

Nonsense
mutation

c.487T

Q163X

Truncated proteins

PEX11B

regulation of peroxisome
division and proliferation

c.64C>T

Q22X

Homozygous

nonsense mutation

No functional protein

Congenital cataracts, mild intellectual
disability, progressive hearing loss,
gastrointestinal problems, recurrent
migraine-like episodes; sensitivity to
illness and long recovery times.

Enlarged and elongated
peroxisomes

Ebberink et al. 2012

*Results from hippocampal cells expressing each mutation separately

VLCFA - very-long-chain fatty acids; TMD - transmembrane domain


Peroxisome
Ins Castro, Joseph Costello, Tina A. Schrader, Afsoon Sadeghi-Azadi, Luis Godinho, Michael Schrader
Lipid
biosynthesis
Glycerol
biosynthesis
Bile acid
synthesis
Fatty acid
-oxidation
Fatty acid
-oxidation
Thermogenesis
Amino acid
metabolism
ROS/NOS
metabolism
Viral innate
immune defense
GPI-anchor
biosynthesis
H O signalling
2 2
in neurons
Purine
catabolism
Peroxisome biogenesis disorders
Single enzyme deciencies
Zellweger spectrum disorders
Rhizomelic chondrodysplasia punctata type I
Rhizomelic chondrodysplasia punctata type II and III
Peroxisomal acyl-CoA oxidase I deciency
X-linked adrenoleukodystrophy
Novel disorders of peroxisome dynamics
Growth & Division
Control broblast
Mff deciency
Pex11 deciency
Multi-step maturation pathway
Minor effects on peroxisome metabolism but strong effects on dynamics
References
Cuesta A et al. (2002) Nat Genet 30:22-25
Ebberink MS et al. (2012) J Med Genet 49:307-313
Huber N et al. (2013) EMBO Rep 14:545-552
Islinger M et al. (2012) Histochem Cell Biol 137:547-574
Niemann A et al. (2005) J Cell Biol 170:1067-1078
Schrader M et al. (2012) Biochim Biophys Acta 1822:1343-1357
Shamseldin HE et al. (2012) J Med Genet 49:234-241
Waterham HR et al. (2007) N Engl J Med 356:1736-1741
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Mitochondria
Defects in PEX genes - essential for organelle biogenesis and protein import
lead to organelle absence or formation of empty peroxisomes/ghosts
Loss of a single peroxisomal function
Dysfunction
DLP1 deciency
N
C
N
C
N
C
N
C
Fis1 Mff
DLP1
Pex11
O2
Fatty acids
Heat
LCFA/MCFA VLCFA
ROS
metabolism
ROS
metabolism
Acyl-CoA
Acetyl-CoA
H2O2
RC
Acetyl-CoA
ATP
Anabolic
reactions
H2O + O2
Cat
O2 -Ox
O2 -Ox
Anabolic
reactions
Division machinery
Antiviral signalling
Vesicle trac (MDVs)
Mff
Fis1
DLP1
MAVS
Elongation
Constriction
Fission
Ether lipid
synthesis
Facial dysmorphism - Hepatomegaly
Ocular abnormalities - Liver brosis
Seizures - Renal cysts - Hearing loss
Neurodevelopmental delay - Hypotonia
Demyelination - Adrenal insufciency
20 m
20 m
20 m
20 m
Peroxisome (dys)function can
affect mitochondria and vice-versa