2. INTRODUCTION
• Mitochondria is a membrane bound cell organelle.
• Main role: Cellular respiration and energy
production - OXPHOS processOXPHOS process
ATP synthesisATP synthesis
MITOCHONDRIAL DNA:MITOCHONDRIAL DNA:
• mtDNA is a circular double stranded DNA with 37 genes which
encodes for
22 tRNAs
2 rRNAs
13 polypeptides (components of electron transport chain)
3. HETEROPLASMY
• For heteroplasmic mtDNA mutations:For heteroplasmic mtDNA mutations: Cell can compensate for reduced wild-type
mtDNA until a certain threshold is met - function of cell become compromised.
• Threshold depends on specific mutation and cell types.
• Ex : neurons have a lower threshold for disease state.
4. MODE OF INHERITANCE
Maternal Inheritance:
At fertilization, all
mitochondria are
contributed by the
oocytes.
The paternal transmission
of mtDNA was reported in
skeletal muscle in a patient
with a mitochondrial
myopathy (Schawarts and
Vissing , 2002)
5. MITOCHONDRIAL DISORDER
• Mitochondrial disorders can arise through :
1. Mutation in mtDNA
2. Mutation in nuclear DNA which encodes mitochondrial
protein.
• Primary mitochondrial diseasePrimary mitochondrial disease:: Diseases involving defects of
oxidative phosphorylation.
• Tissues with high energy demands such as brain tissues, heart
muscle, skeletal muscles are more severely affected.
9. DIAGNOSIS
• FAMILY HISTORY: Inheritance pattern (maternal inheritance)
• CLINICAL EVALUATION: Signs and symptoms of mitochondrial
disease.
• LABORATORY: Blood lactate and pyruvate levels,
Cerebrospinal fluid lactate and pyruvate levels.
• MUSCLE BIOPSY: Hallmark of mitochondrial dysfunction –
Ragged Red Fiber (RRF)
• NEURORADIOLOGY: EEG, Brain MRI and spectroscopy
When clinical features, family history, muscle morphology, biochemical
data suggest mtDNA mutation then molecular genetic studies are done.
• MOLECULAR GENETICS: Southern blot analysis
10. GENERAL PRINCIPLES OF
TREATMENT
TWO THERAPY APPROACHES:
– One therapeutic approach has been aimed at the removal of noxious
metabolites, in particular lactic acid.
– Another approach is supplementation of respiratory chain
components such as Coenzyme Q10 that may increase the
mitochondrial activity.
• Symptomatic management:
– Seizures (antiepileptic drugs, avoid valproic acid)
– Dystonia (diazepam, botulinum toxin [focal], trihexyphenidyl)
– Spasticity (baclofen, botulinum toxin [focal])
– Nutritional Deficiencies
11. IMPACT OF MITOCHONDRIAL DEFECT
IN FEMALE INFERTILITY
GENERAL FUNCTION OF MITOCHONDRIA IN OOCYTES:
• Mitochondria are important for oocyte maturation, fertilization, and
pre-implantation development.
• They contribute ATP for energy consuming events such as nuclear envelope
breakdown, and microtubule assembly and disassembly for meiotic and mitotic
spindle assembly.
• Perinuclear accumulation of mitochondria is a positive sign of oocyte quality.
INCASE OF mtDNA MUTATIONS:
• Mitochondrial dysfunction associated with infertility have been shown in women
affected by metabolic disorders (diabetes and obesity) Oocyte aging.
• A threshold level of mtDNA is necessary to support fertilization and embryo
development.
• Oocyte mitochondria with mutations may pass these mutations to the offspring
12. IMPACT OF MITOCHONDRIAL
DEFECT IN MALE INFERTILITY
• Sperms require a great deal of ATP for the flagellum to move
around in the early phase of fertilization.
• Male infertility is associated with asthenozoospermia or
oligoasthenozoospermia and has been reported in patients suffering
from typical mtDNA diseases, involving point mutations or multiple
deletions of mtDNA.
• Deletion of sperm mitochondria-associated cysteine-rich protein, a
structural protein associated with the keratinous capsules of sperm
mitochondria, seriously affects sperm motility despite having normal
sperm morphology.
• It has been shown that high levels of A3243G mtDNA mutant
strongly correlate with low sperm motility.
15. REFERENCES
• Gorman, G. S., & Chinnery, P. F. (2015). Mitochondrial diseases.
Oxford Medicine Online.
• Gorman, G. S., & Chinnery, P. F. (2015). Mitochondrial diseases. Oxford
Medicine Online.
• Chinnery PF. Mitochondrial Disorders Overview. 2000 Jun 8 [Updated 2014 Aug
14]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews®
[Internet]. Seattle (WA): University of Washington, Seattle; 1993-2019.
• Shanske AL, Shanske S, DiMauro S. The Other Human Genome. Arch Pediatr
Adolesc Med. 2001;155(11):1210–1216.
• Schatten, H., Sun, Q. Y., & Prather, R. (2014). The impact of mitochondrial
function/dysfunction on IVF and new treatment possibilities for
infertility. Reproductive biology and endocrinology : RB&E, 12, 111.
