A branch of medicine dealing with diseases and metabolic disorders that affect mitochondria. Focusing on diagnosing and treatment of wide range of these diseases. The symptom of these diseases varies from metabolic-induced developmental delay to complex problems that involve many body systems.

1. Introduction
to
Mitochondrial Medicine
Assistant Professor
Dr. Muhammad A. Ahmed Al-Kataan
Ph.D. Molecular Biochemistry and Stem Cell Biology
Keele University - UK
m.a.a.ahmed@uomosul.edu.iq

2. Mitochondrial-Medicine
A branch of medicine dealing with diseases and
metabolic disorders that affect mitochondria.
Focusing on diagnosing and treatment of wide
range of these diseases. The symptom of these
diseases varies from metabolic-induced
developmental delay to complex problems that
involve many body systems.
As the powerhouse of the cell, the mitochondrion
is essential for life. A large body of research in
recent years has established that mitochondria
passively producing ATP, sense and respond to
changing cellular environments and stresses.

3. Picard et al., 2016

4. Richard Altmann
(Frist observation
1894)
Carl Benda
(term Mitochondria 1898)
Benjamin F. Kingsbury,
(Related Mito with cell
respiration 1912)
David Keilin
(Cytochromes of
respiratory chain 1925)
Rolf Luft
(Father of mito-medcicne
1962)
Historical review

5. Picard et al., 2016

6. What are Mitochondria
A double-membrane structured organelle
contains the machinery that is needed for the
produce of ATP, and to fulfil their roles in
apoptosis, calcium homeostasis and the
formation of iron sulphur clusters along with
many other functions.
Mitochondria have it own DNA and can encode
some of their own proteins
Undergo continuous Fission and Fusion.
The hypothesis of mitochondria origin
“endosymbiotic theory” was proposed by
Margulis (1971)
M. Ahmed 2018

7. mt-DNA
37 genes
n-DNA
1000 of
20000 genes
13
Subunit
77
Subunit
Mitochondria
Respiratory Chain
One organelle of two genome

8. Mitochondria components
FunctionStructure
Separates the contents of the mitochondrion from the rest
of the cell
Outer mitochondrial membrane
Internal cytosol-like area that contains the enzymes for the
link reaction & Krebs Cycle
Matrix
Tubular regions surrounded by membranes increasing
surface area for oxidative phosphorylation
Cristae
Contains the carriers for the ETC & ATP synthase for
chemiosmosis
Inner mitochondrial membrane
Reservoir for hydrogen ions (protons), the high
concentration of hydrogen ions is necessary for
chemiosmosis
Space between inner & outer
membranes
http://teachmephysiology.co
m

9. Role of Mitochondria
Energy conversion
Pyruvate decarboxylation
Fatty acid oxidation
Respiration
Apoptosis
ROS signaling
Ca2+ homeostasis
Regulation of cellular
electrolytes Flux
Protects DNA
Formation of Iron
sulphur clusters
M. Ahmed 2018

10. Genomic
n DNA
mt DNA
Defect/
mutation
Cell stress
Virus
Chemical
Drug
Toxins
Defected mt-DNA
Energy , ROS
Δ AP, Δ Ca+2
Diseases
Causes of Mitochondrial
dysfunction

11. Mitochondria gene defect
The frequency of primary mitochondrial defect is
1:5000 mainly affecting OXPHOS pathway.
In fact, 1:200 of new bone baby have certain
degree of abnormality in their mt-DNA so they
have the potential to develop primary mito-
pathy (Koenig et al., 2008).
But the condition manifested only in those who
pass the “abnormality threshold”
https://ghr.nlm.nih.gov/mitochondri
al-dna

12. A. Defects of substrate transport
Carnitine-palmitoyl-transferase deficiency
Primary systemic or muscle carnitine deficiency
Secondary carnitine deficiency
B. Defects of substrate utilization
Pyruvate dehydrogenase complex (PDC)
deficiency
Pyruvate-decarboxylase deficiency
Defects of the β-oxidation
Defects of the Kreb’s cycle
Fumarase deficiency
Ketoglutarate dehydrogenase deficiency
Aconitase deficiency
C. Defects of the oxidation-
phosphorylation coupling
Luft’s syndrome (loose coupling and
hypermetabolism)
D. Defects of the Respiratory chain
(RC)
Complex I, II, III, IV, or V defect
Combined defects of the RC components
mt-DNA defect
lead to Mito-diseases

13. Russell et al,2013

14. A. Defects of Respiratory Chain complex
 Complex II defect described by A. Munnich 1955.
 Complex I defect described by many groups from 1995-2001 as Leigh syndrome.
 Nijmegen group describe role of NDUFS1 in RC disorders.
B. Defects n-DNA / mt-DNA Intergenomic communication
C. Defects in mitochondrial protein translation
n-DNA defect
lead to Mito-diseases

15. Disease conditions related to
Mitochondrial dysfunction
Cerebral palsy
Development failure
Autism
Cardiomyopathy
Alzheimer's
Chronic Fatigue
Muscle dystrophy
Atypical learning
Disability
Diabetes
Parkinson'sCancer Abnormal immunity

16. Mitochondrial dysfunction
manifestation
In addition to history issues such as maternal health, obstetric history, family
history of neonatal or childhood deaths, deafness, diabetes, cardiac disease,
visual impairment, and developmental delay should be particularly addressed.
Possible manifestations on visceral organs are summarized:
1. Neuromuscular system e.g. facial dysmorphism, mental retardation,
dementia, impaired visual acuity, visual field defect, deafness, dysarthria, dry
mouth, reduced gag reflex, wasting, hypotonia, reduced deep tendon

17. 2. Eye - pigmentary retinopathy, optic atrophy, cataract, and glaucoma.
3. Endocrine system – short stature, developmental delay, polyphagia, failure to thrive,
thrive, hypopituitarism, diabetes mellitus, diabetes insipidus, hypoglycemia, thyroid
and parathyroid dysfunction, amenorrhea, hypogonadism, delayed puberty .
4. Heart – cardiomyopathy, rhythm abnormalities, left ventricular hyper-trabeculation.
trabeculation.
5. Gastrointestinal –dysphagia, gastrointestinal dysmotility, pseudo-obstruction,
recurrent vomiting, hepatopathy, anorexia.
6. Kidneys – renal cysts, tubulopathy, Toni-Debre-Fanconi syndrome.
7. Blood – anemia, leucopenia, thrombocytopenia, eosinophilia

18. In addition, certain drugs impair mitochondrial functions like aspirin,
alcohol, valproate, barbiturates (block complex I), tetracyclines,
chloramphenicol (reduce mitochondrial protein synthesis), doxorubicin
zidovudine (causes mtDNA depletion), while vitamin C and E exert
protective effects. Thus a thorough drug history is important. Recently,
steroid-induced myopathy has been proposed to be a mitochondrial
disorder There may be an increased sensitivity to general anesthetic agents
like etomidate and thiopental.

21. Sited from http://www.mitoaction.org/

22. Diagnosis
The diagnostic approach for diagnosis of mitochondrial dysfunction include
clinical, electrophysiological, imaging, histological,
biochemical and genetic investigations.
Myopathy with or without lactic acidosis is the most common presenting
feature.
Combination of clinical features like deafness, cardiomyopathy and diabetes
together with encephalopathy and myopathy are regarded as red flags for
these cases.
Stage 1
Metabolic testing:
Blood
Urine
CSF
Stage 2
Muscle testing:
Liver Tissue and Respirometry
Muscle pathology OXPHOS
enzymes and protein chemistry
Stage 3
Genetic testing:
mt-DNA
n-DNA

23. The most important biochemical parameters are serum and cerebrospinal
fluid lactate and pyruvate. Both are frequently increased at rest.
The serum lactate/ pyruvate ratio is increased >20 times.
There is an exaggerated accumulation of extracellular lactate during
aerobic exercise compared to healthy subjects (‘lactate stress test’).
The ‘ischemic forearm test’ is as sensitive as muscle biopsy and based on
decreased oxygen extraction from capillary blood, resulting in high O2
saturation in venous effluent blood from working muscles.
Approach for Mitochondrial
Diseases Diagnosis

24. Example of Biochemical analysis
For Mitochondrial dysfunction
Acyl carnitines
(Plasma)
Organic acid
(urine)
Amino acid
(Plasma/ CSF)
Low free carnitineHigh TCA intermediatesHigh Alanine
High acyl free carnitine ratioHigh Ethyl malonateHigh Glycine
Elevation of substrate for fatty acid
oxidation
3-methyl glutaconateΔ Proline
Di carboxylic acidsΔ Tyrosine

25. Muscle biopsy is the most helpful diagnostic procedure for evaluation. Muscle
tissue should be investigated for :
i) Routine light microscopy including modified Gomori trichrome stain
(ragged-red fibers).
ii) Immunohistochemistry including COX (cyclooxygenase), succinate
dehydrogenase, NADH, ATPase and Mitotrackers.

26. M. Ahmed 2018

28. iii) Electron microscopy to view any abnormal mitochondrial structure.
iv) Polarography determines the RC activity, the OXPHOS activity, the
integrity of mitochondrial membranes, and the efficiency of substrate
transport.

29. v) Immunoblot measures the molecular weight of various proteins
vi) Genetic testing should be carried out only if the clinical features are highly
suggestive of one of the classical syndromes.
Sequencing of the entire mtDNA should be carried out only from muscle mtDNA.
Evidence of new mtDNA mutations is best provided by PCR (Restriction fragment
length polymorphism (RFLP) analysis.

30. Aims

31. 1. Establish of Mitochondrial medicine center that will include medical and
research staff who have deep insight knowledge and understanding in
diagnose and treatment of mitochondrial diseases and has explicit
permission from the health office and patients to use their data to carry
out further work.
2. Formation of a steering group within the university responsible for the
execution of this ambitious project. This group will focus on
mitochondrial defect – both inherited and acquired- and form a
nucleus for training more scientist in this branch and collaborate with
project supporting Universities to publish researches
3. Start collaboration with Ministry of health to introduce this branch of
medicine to medical staff through meeting and workshop about the
methods of diagnosis and treating such conditions.

32. 4. Work with other Iraqi Universities to transfer mitochondrial medicine
knowledge to provide best medical services for all Iraqi patients.
5. Work with other mitochondrial medicine organization around the world in
collaboration with IMP to build mitochondrial diseases database which will
facilitate the diagnosis in the future.
6. Establish communication channels with project supporting countries to
help us in the diagnosis and treating our patient until we have the ability to
do this by ourselves.

34. THE INTERNATIONAL VOICE OF PATIENTS
www.mitopatients.org

35. Spain
Netherlands
Germany
Great Britain
Netherlands
USA
Great Britain
France
USA
Belgium
Italy
Australia

36. • REPRESENTING 8,000 – 10,000 MITOCHONDRIAL
PATIENTS ON THREE CONTINENTS
• REACHING OUT TO MITO PATIENTS WHEREVER THEY
ARE
• WWW.MITOPATIENTS.ORG

37. THE MOSUL PROJECT FOR MITOCHONDRIAL
MEDICINE IS WONDERFUL NEWS FOR MITO
PATIENTS IN IRAQ
ALL IMP MEMBERS REACH OUT TO
MITOCHONDRIAL PATIENTS IN IRAQ:
• TO SHARE KNOWLEDGE AND EXPERIENCE
• TO SUPPORT THE ORGANISATION OF PATIENT
GROUPS

38. Congratulations!
WE WISH YOU GOOD LUCK ON BEHALF OF THE
INTERNATIONAL COMMUNITY OF
MITOCHONDRIAL PATIENTS

39. References
Munich A, Rotig A, Chretien D, et al. Clinical presentation of mitochondrial disorders in childhood. J Inherit
Metab Dis 1996; 19: 521-7
Chinnery PF, Johnson MA, Wardell Tm, et al. The epidemiology of pathogenic mitochondrial DNA mutations.
Ann Neurol 2000; 48:188-93.
The Mitochondrial Disease Foundation (2003). Pittsburgh. info@umdf.org
Kerr DS. Protean manifestations of mitochondrial diseases: a minireview. J Pediatr Hematol Oncol 1997; 19:
279-86.
Leonard JV, Schapira AHV. Mitochondrial respiratory chain disorders I: mitochondrial DNA defects. Lancet
2000; 355: 299-304.
Leonard JV, Schapira AHV. Mitochondrial respiratory chain disorders II. Neurodegenerative disorders and
nuclear gene defects. Lancet 2000; 355: 389-394.

40. Schapira AHV. The ‘new’ mitochondrial disorders. J Neurol Neurosurg Psychiatry 2002; 72: 144-9.
Bandyopadhyay SK, Dutta A. Mitochondrial hepatopathies. J Assoc Physicians India 2005; 55; 665-
Singhal N, Gupta BS, Saigal R, et al. Mitochondrial diseases: an overview of genetics, pathogenesis,
clinical features and an approach to diagnosis and treatment. J Postgrad Med 2000; 46: 224-30.
Finsterer J, Stratil U, Bittner R, et al. Increased sensitivity to rocuronium and atracurium in
myopathy. Can J Anaesth 1998; 45: 781-4.
Mitsui T, Azuma H, Nagasawa M, et al. Chronic corticosteroid administration causes mitochondrial
dysfunction in skeletal muscle.J Neurol 2002; 249: 1004-9.
Gillis L, Kaye E. Diagnosis and management of mitochondrial diseases. Pediatr Clin N Am 2002; 49:
19.
Finsterer J, Milvay E. Lactate stress testing in 155 patients with respiratory chain disorders. Can J
Sci 2002; 29: 49-53.

41. Jensen TD, Kazemi-Esfarjani P, Skomorowska E, et al. A forearm screening test for mitochondrial myopathy.
Neurology 2002; 58: 1533-8.
Fadic R, Johns DR. Clinical spectrum of mitochondrial diseases.Semin Neurol 1996; 16: 11-22.
McFarland R, Taylor RW, Turnbull DM. The neurology of mitochondrial DNA diseases. Lancet Neurol 2002; 1:
343-51.
Wolf IN, Smeitink JAN. Mitochondrial disorders. Neurology 2002; 59: 1402-5.
Weissig V, Cheng S-M, D’Souza GGM. Mitochondrial pharmaceutics. Mitochondrion 2004; 3: 229-44.
Schwartz M, Vissing JN. Paternal inheritance of mitochondrial DNA. N Engl J Med 2002; 347: 576-80.
Luft R, The development of mitochondrial medicine. Proc Natl Acad Sci U S A 1994; 91: 8731-8.

42. Many
thanks

43. Project stage
and
Workflow chart

44. Stage One
Introduce the term to the health professional staff
Stage Two
In collaboration in genetic diagnosis team in Newcastle
University – Mitochondrial center, the type of genetic
defect will diagnose for Iraqi patients.
Stage Three
Work with IMP and other organization in project
supporting countries to help us to find proper treatment
options to our patients.
Project Stages

45. Iben Al-Atheer
Ped. Hospital
Al-Khinsaa
Ped. Hospital
Mitochondrial research center
University of Mosul
Health centers and Primary Care units
around the Country
Follow chart for mito-patient care

46. Clinical team
Pediatrics
Internal medicine
Neurology
ENT
Ophthalmology
Pharmacology
Cardiology
Psychiatry
Genetic& Biochemistry
Team
Molecular Biochemistry
Genetics
Immunology
Histopathology
Project Supporting Universities and organizations
Program co-
Ordinator/ patient
registration

47. Discussion
we are honor to receive any
questions and suggestions