Human mtDNA

D-loop region

tRNA (22 ×)

HSP1

F

V

I

M

W

P

Q

A

N

C

S1 or S (UCN)

Y

L1 or L (UUR)

HSP2 O H

OL

MTRNR1

MTRNR2

LSP

MTND2

MTND1

Mitochondrial medicine

Mitochondrial medicineRESEARCH ARTICLES

TFE3 regulates whole-body energy metabolism in cooperation with TFEB Nunzia Pastore, Andrea Ballabio and colleagues

TFE3 plays a critical role in the metabolic response to environmental cues by regulating glucose homeostasis, lipid metabolism and mitochondrial dynamics.EMBO Molecular Medicine Published online 10.03.2017 DOI: 10.15252/emmm.201607204

CoQ deficiency causes disruption of mitochondrial sulfide oxidation, a new pathomechanism associated with this syndrome Marta Luna-Sánchez, Luis C López and colleagues

Disruption of the mitochondrial hydrogen sulfide oxidation pathway is identified as a new pathomechanism associated with primary CoQ deficiency. These findings may help explain the clinical heterogeneity of this syndromeEMBO Molecular Medicine Published online 17.11.2016 DOI: 10.15252/emmm.201606345

Coenzyme Q deficiency causes impairment of the sulfide oxidation pathway Marcello Ziosi, Catarina M Quinzii and colleagues

Coenzyme Q (CoQ) is an electron acceptor for sulfide-quinone reductase (SQR), the first enzyme of the hydrogen sulfide oxidation pathway. Lack of CoQ is here shown to cause impairment of hydrogen sulfide oxidation in vitro and in vivo.EMBO Molecular Medicine Published online 17.11.2016 DOI: 10.15252/emmm.201606356

Modified Atkins diet induces subacute selective ragged-red-fiber lysis in mitochondrial myopathy patients Sofia Ahola, Anu Suomalainen and colleagues

High-fat, low-carbohydrate modified Atkins diet (mAD) is a common weight-loss method, found to ameliorate mitochondrial myopathy in mice. In human patients, mAD induces muscle damage, especially of ragged-red fibers, the most affected by the disease.EMBO Molecular Medicine Published online 19.09.2016 DOI: 10.15252/emmm.201606592

Coenzyme A corrects pathological defects in human neurons of PANK2-associated neurodegeneration Daniel I Orellana, Sonia Levi and colleagues

Mutations in PANK2 cause PKAN disease. This belongs to a group of disorders characterized by progressive neurodegeneration and excessive iron deposition in the brain. PANK2 enzyme catalyzes the first step in CoA synthesis. iPSC-derived neurons from PKAN patients display abnormal phenotypes.EMBO Molecular Medicine Published online 11.08.2016 DOI: 10.15252/emmm.201606391

SLC25A46 is required for mitochondrial lipid homeostasis and cristae maintenance and is responsible for Leigh syndrome Alexandre Janer, Eric A Shoubridge and colleagues

Whole-exome sequencing in a Leigh syndrome patient identified mutations in SLC25A46, a degenerate member of the mitochondrial metabolite transport family, linking altered mitochondrial dynamics to early-onset neurodegenerative disease.EMBO Molecular Medicine Published online 07.07.2016 DOI: 10.15252/emmm.201506159

Reduction in mitochondrial iron alleviates cardiac damage during injury Hsiang-Chun Chang, HosseinArdehali and colleagues

Modulation of mitochondrial iron is shown to be a viable therapeutic approach against ischemic heart disease and heart failure, highlighting the need to develop more targeted iron chelators.EMBO Molecular Medicine Published online 19.02.2016 DOI: 10.15252/emmm.201505748

Defective PITRM1 mitochondrial peptidase is associated with Aβ amyloidotic neurodegeneration Dario Brunetti, Laurence A Bindoff

A clinically peculiar neurodegenerative disorder in humans was indentified and shown to be caused by a pathogenic homozygous mutation in PITRM1, encoding an oligopeptidase of the mitochondrial inner compartment. The neuropathology of a PITRM1−/+ mouse provides genetic evidence that Aβ is present within mitochondria, and demonstrates a link between impaired PITRM1 activity and Aβ amyloidotic neurodegeneration in mammals.EMBO Molecular Medicine Published online 23.12.2015DOI: 10.15252/emmm.201505894

REVIEWS

Mitochondrial disease in adults: what’s old and what’s new? Patrick F Chinnery

EMBO Molecular Medicine Published online 26.11.2015 DOI: 10.15252/emmm.201505079

Mitochondrial disorders in children: toward development of small-molecule treatment strategies Werner JH Koopman, Julien Beyrath, Cheuk-Wing Fung, Saskia Koene, Richard J Rodenburg, Peter HGM Willems, Jan AM Smeitink

EMBO Molecular Medicine Published online 07.03.2016 DOI: 10.15252/emmm.201506131

mtDNA

BRAIN

• Encephalopathy

• Stroke-like episodes

• Epilepsy

• Dementia

EYE

• Ophthalmoplegia

• Ptosis

• Optic neuropathy

• Pigmentary retinopathy

EAR

• Sensorineural deafness

NERVE

• Axonal peripheral neuropathy

• Dorsal root ganglionopathy

SPINAL CORD

• Spastic paraplegia

ENDOCRINE

• Diabetes mellitus

• Hypopara- thyroidism

SKIN

• Lipomatosis

RANGE OFCLINICALFEATURES

HEART

• Cardiomyopathy

• Conduction defects

KIDNEY

• Renal tubulopathy

MUSCLE

• Proximal and distal myopathy

GUT

• Constipation

• Pseudo- obstruction

Human mtDNA

D-loop region

Control region

tRNA (22×)

HSP1

F

V

IM

W

D

GR

K

H

E

P

Q

ANC

S1 or S(UCN)

L2 or L(CUN) S2 or S(AGR)

Y

L1 or L(UUR)

HSP2 OH

OL

MTCYB

MTRNR1

MTRNR2

MTND5

MTND4

MTND6

LSP

MTND4L

MTND3

MTND2

MTCO1

MTCO2

MTND1

MTCO3

MTATP6MTATP8

T

RESPIRATORY CHAIN

3H+in

3H+out

V

ADP+Pi ATP

NAD+

+ 2H+

NADH+ H+

QH2

O2·–

Q

4H+in

4H+out

QQH2

Succinate

Fumarate

II

I

2Q2QH2

½O2

H2O

4H+in

2H+out

IV

2H+in

4H+out

IIIQ

QH2

2 Cyt c

e–

e–

m

Intermembranespace

Matrix

IMM

OMM

O2·–

MtDNAmaintenance

MtDNAtranscription and translation

Complexassembly

II IIIIII cII IVIV VV

Nuclear DNA

Mito

chon

drio

n

ELECTRON TRANSPORT CHAIN (ETC)

OXIDATIVE PHOSPHORYLATION (OXPHOS) SYSTEM

~pH 8.4 – – – – –

Proton-motiveforce (PMF)

ΔpH ΔΨ

ANT

+

ATP4–

ATP4–

ADP3–

ADP3–

Pi (PO43– )

Pi

CV PiTETC

~pH 7.4 +++++

OtherUCP

MIM

IMS

Mat

rix

H+

H+ H+

H+ H+H+

MIM

IMS

Mat

rix

Pyr

NADH FADH2

MIMMIMIMS

MOMMOM

Glc

Glycolysis

TCAMatrix

Pyr

FAs

Lac

ATP

C

A B

• ETF-ubiquinone oxidoreductase• Dihydroorotate dehydrogenase• s,n-glycerophosphate dehydrogenase

• Pre-protein import• Ion and metabolite exchange• Mitochondrial dynamics• Apoptosis induction• ROS generation

H+

c

• Mo-pterin• B-type heme

O2 H2O

CIV

H+

CIIIQ

FADH2FAD

CII

NADHNAD+

CI

Gln

OXPHOS

MPC

e–

e–

We want to meet you!Discuss your latest work with the EMBO Molecular Medicine editor at this meeting

Roberto BuccioneEditorroberto.buccione@embo.org

embomolmed.embopress.org