Function

Peroxisome dynamics in health and disease

Eukaryo�c cells contain dis�nct membrane-bound organelles, which compartmentalise cellular proteins to fulfil a variety of vital func�ons. Many organelles such as peroxisomes have long been regarded as isolated and sta�c en��es, but we provided evidence that they are highly dynamic. Their complex behaviour determines organelle number, distribu�on, inheritance, turnover, metabolic coopera�on and organelle interac�on. Our discovery and molecular characterisa�on of peroxisome morphology proteins regula�ng these processes has now supported the iden�fica�on, 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

DNM1LDLP1

mitochondrial and peroxisomal membrane fission

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 intensityon brain MRI of the globus pallidus, motor and speech deficits, mild hypertonia, borderline microcephaly,pale optic discs

Elongated peroxisomesand 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 first decade, sensory nerveaction 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 peroxisomedivision 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 toillness 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

Inês Castro, Joseph Costello, Tina A. Schrader, Afsoon Sadeghi-Azadi, Luis Godinho, Michael Schrader

Lipidbiosynthesis

Glycerolbiosynthesis

Bile acidsynthesis

Fatty acidα-oxidation

Fatty acidβ-oxidation

Thermogenesis

Amino acidmetabolism

ROS/NOSmetabolism

Viral innateimmune defense

GPI-anchorbiosynthesis

H O signalling2 2

in neurons

Purinecatabolism

Peroxisome biogenesis disorders

Single enzyme deficiencies

Zellweger spectrum disorders

Rhizomelic chondrodysplasia punctata type I

Rhizomelic chondrodysplasia punctata type II and III

Peroxisomal acyl-CoA oxidase I deficiency

X-linked adrenoleukodystrophy

Novel disorders of peroxisome dynamicsGrowth & Division Control fibroblast

Mff deficiency

Pex11β deficiency

Multi-step maturation pathwayMinor effects on peroxisome metabolism but strong effects on dynamics

ReferencesCuesta A et al. (2002) Nat Genet 30:22-25Ebberink MS et al. (2012) J Med Genet 49:307-313Huber N et al. (2013) EMBO Rep 14:545-552Islinger M et al. (2012) Histochem Cell Biol 137:547-574

Niemann A et al. (2005) J Cell Biol 170:1067-1078Schrader M et al. (2012) Biochim Biophys Acta 1822:1343-1357Shamseldin HE et al. (2012) J Med Genet 49:234-241Waterham HR et al. (2007) N Engl J Med 356:1736-1741

Lip

id a

nd

pro

tein

im

po

rt

Mitochondria

Defects in PEX genes - essential for organelle biogenesis and protein importlead to organelle absence or formation of empty peroxisomes/ghosts

Loss of a single peroxisomal function

Dysfunction

DLP1 deficiency

N

C

N

C

N

C

N

C

Fis1 Mff

DLP1

Pex11β

O2

Fatty acids

Heat

LCFA/MCFAVLCFA

ROS

metabolism

ROS

metabolism

Acyl-CoA

Acetyl-CoA

H2O2

RC

Acetyl-CoA

ATPAnabolicreactions

H2O + O2

Cat

O2 β-OxO2β-Ox

Anabolicreactions

Division machinery

Antiviral signalling

Vesicle traffic (MDVs)

Mff

Fis1DLP1

MAVS

Elongation

Constriction

Fission

Ether lipidsynthesis

Facial dysmorphism - HepatomegalyOcular abnormalities - Liver fibrosis

Seizures - Renal cysts - Hearing lossNeurodevelopmental delay - HypotoniaDemyelination - Adrenal insufficiency

20 µm

20 µm

20 µm

20 µm

Peroxisome (dys)function canaffect mitochondria and vice-versa