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1. FACTORS INFLUENCING LEIGH
SYNDROME
Monearah Alotaibi
Fatima Albogami

2. Key Points About Leigh
Syndrome (LS)
•LS results from mutations that disrupt the electron transport chain (ETC) in the mitochondria.
•When the ETC becomes overburdened and oxidative dysfunction persists, pathogenic processes are
triggered.
•The mitochondrion acts as a hub for oxygen and electron-rich molecules, so disrupted electron and
proton flow leads to:
•Formation of reactive oxygen species (ROS)
•Formation of superoxide
•These changes activate stress and inflammatory responses; chronic activation can result in:
•Cell death
•Development of LS symptoms
•This section introduces the ETC and explains how defects in any complex contribute to LS pathology.
•It focuses mainly on ETC defects caused by mtDNA mutations, which are responsible for most reported
LS cases.

3. Complex I (NADH:Ubiquinone
Oxidoreductase)
•Complex I is the largest and first component of the mitochondrial electron transport chain (ETC).
•It contains more than 45 subunits
•mtDNA encodes 7 subunits: MTND1–MTND6 and MTND4L.
•nDNA encodes the remaining structural subunits and assembly factors.
 Function:
 Oxidizes NADH (from glycolysis, Krebs cycle, β-oxidation).
 Transfers electrons to ubiquinone (Q).
 Couples this redox reaction to proton pumping across the inner mitochondrial membrane.
•Due to its large size and position in the OXPHOS pathway, Complex I defects cause severe respiratory chain
dysfunction.
• Complex I deficiency accounts for most Leigh Syndrome (LS) cases
 Clinical presentation varies widely:
• May appear at any age.
• Symptoms range from isolated myopathy or liver disease to multisystem disorders

4. Complex I Gene Mutations
Linked to Leigh Syndrome (LS)
• Approximately 14 nDNA genes encoding structural and assembly
factor subunits of Complex I have been implicated in LS.
• Three mtDNA genes (MTND2, MTND3, MTND5) are primarily
associated with LS.
• MTND3 and MTND5 mutations are the most common mtDNA
mutations linked to LS.

5. MTND Mutations Linked to
Leigh Syndrome (LS)
1. MTND3 gene mutations:
• m.10158T>C
• m.10191T>C
• m.10197G>A
2. MTND5 gene mutations:
• m.12706T>C
• m.13513G>A
• m.13514A>G
3. MTND6 gene mutations:
• m.14459G>A
• m.14487T>C

6. MTND Mutations and Their
Functional Impact on Complex I
Gene Mutation Amino Acid Change / Effect Functional Consequence Notes / Clinical Impact
MTND3 m.10158T>C Serine replaces Proline (codon 34)
Slightly affects assembly,
drastically reduces enzymatic
activity
Causes LS
MTND3 m.10191T>C Serine replaces Proline (codon 45)
Slightly affects assembly,
drastically reduces enzymatic
activity
Causes LS
MTND3 m.10197G>A
Alanine replaces Threonine (codon
47)
Slightly affects assembly,
drastically reduces enzymatic
activity
Causes LS
MTND5 m.12706T>C – Impairs Complex I assembly &
activity
Can cause LS at low mutant loads
(<50%)
MTND5 m.13513G>A – Impairs Complex I assembly &
activity
Can cause LS at low mutant loads
(<50%)
MTND5 m.13514A>G – – LS / other Complex I disorders
MTND6 m.14459G>A – –
LS / other Complex I
disorders(MELAS)
MTND6 m.14487T>C – – LS / other Complex I disorders

7. Complex II(succinate-coenzyme
Q reductase)
• The smallest complex in the ETC, composed of four subunits (SDHA to SDHD), all encoded
by nuclear DNA.
• Location and Role:
• Located in the inner mitochondrial membrane.
• Participates in both the citric acid cycle and electron transport chain (ETC).
• SDHA: Oxidizes succinate and reduces its flavin cofactor (FAD).
• SDHB: Transfers electrons to ubiquinone in coordination with SDHA.
• Mutations:
• Mutations in Complex II are very rare compared to Complex I.
• More than 10 autosomal recessive mutations in SDHA have been reported to cause LS,
Leigh-like syndromes, and other mitochondrial disorders.
• Mutations in SDHAF1 (assembly factor), SDHB, and SDHD have also been reported to cause
LS or LS-like symptoms.
• SDHC has not yet been reported to be involved in LS.

8. Complex III
( Ubiquinol-
Cytochrome
c Reductase)
• Subunits:
• Complex III has 11 structural subunits.
• Only Cytochrome b (MT-CYB) is
encoded by mitochondrial DNA.
• Location and Role:
• Located in the inner mitochondrial
membrane.
• Transfers electrons from succinate and
NADH dehydrogenases to cytochrome
c.
• The energy from this electron transfer
is used to pump protons across the
inner membrane, creating the proton
gradient necessary for OXPHOS.
• Mutations
• Complex III deficiencies are rare

9. Complex III
deficiency
Gene /
Subunit
Mutation Effect Phenotype / Notes
MT-CYB m.14792C>G p.His16Asp Rare
ND6 m.14459G>A p.Ala72Val
Primary LS cause in
the reported patient
BCS1L
(nDNA)
Various
mutations
Impaired
assembly of
Complex III
Most common
nDNA-related LS
cases
TTC19
(nDNA)
Rare mutations
Impaired
assembly
factor
Rare LS cases
UQCRB
(nDNA)
Reported
mutations
Impaired
subunit VI
function
LS or LS-like
symptoms
UQCRQ
(nDNA)
c.208C>T p.Ser45Phe
LS-like symptoms;
may also reduce
Complex I activity

10. Complex IV(Cytochrome c
Oxidase, COX)
• Location and Role:
• Embedded in the inner mitochondrial membrane.
• Terminal enzyme of the electron transport chain (ETC).
• Transfers electrons from reduced cytochrome c to molecular oxygen.
• Subunits:
• Total of 13 subunits:
– 3 mtDNA-encoded (MT-COX1, MT-COX2, MT-COX3) → catalytic
subunits.
– 10 nuclear-encoded subunits → involved in assembly and
biogenesis of the complex.

11. • Mutations and Clinical
Importance:
• Most COX deficiencies are
caused by nuclear DNA
mutations.
• About 15% of LS cases are due
to isolated COX deficiency.
Gene /
Subunit Mutation Effect Phenotype / Notes
SURF1
(nDNA)
Various
mutations
Impaired assembly
of Complex IV
LS and other
metabolic disorders;
common COX-
related LS
LRPPRC
(nDNA)
A354V
Affects post-
transcriptional
regulation of
mitochondrial gene
expression
LS, high early
mortality; founder
mutation in French-
Canadian population

12. Complex V (ATP Synthase)
•Location and Role:
•Terminal complex of the OXPHOS pathway.
•Composed of Fo domain (hydrophobic, inner membrane) and F1
domain (ATPase, in matrix).
•Uses the proton gradient generated by Complexes I, III, and IV to
convert ADP + Pi → ATP.
•Subunits:
•19 subunits in total:
•2 mtDNA-encoded → part of Fo domain.
•17 nDNA-encoded → assembly and function.

13. Mutations in Complex V
Gene / Subunit Mutation Effect Phenotype / Notes
MTATP6 (mtDNA) m.8993T>G
Leu156 → Arg; destabilizes
catalytic site
MILS (Maternally Inherited
Leigh Syndrome); severe
phenotype
MTATP6 (mtDNA) m.8993T>C Leu156 → Pro; mild effect on
catalytic site
NARP (Neuropathy, Ataxia,
Retinitis Pigmentosa); mild,
late-onset, slower
progression
MTATP6 (mtDNA) m.9185T>C
Leu220 → Pro; interferes
with proton pump
LS onset often triggered by
fever or viral infection;
variable phenotype; some
improvement with hypoxia
treatment

15. Strengths
1. comprehensive Content
•The article covers all five ETC complexes in detail.
•Includes both nuclear-encoded and mitochondrial-encoded
genes and the mutations associated with each complex.
2. High Scientific Accuracy:
•Provides detailed explanations of how mutations affect complex
function, ATP production
3.Focus on Clinical Relevance
Links mutations to clinical symptoms such as LS, NARP, and MILS
4. biochemical Mechanism Explanation
highlights modifying factors such as amino acid type and mutation
location

16. Weaknesses
1. Excessive Length and Detail:
– The article is very long and contains detailed information that can overwhelm non-specialist
readers.
2. Limited Visual Aids:
– Mostly textual information with minimal use of tables or diagrams.
– Understanding could be improved with illustrations for each complex and its mutations.
3. Population and Genetic Variation Not Fully Addressed
Some population-specific differences are mentioned (e.g., LRPPRC in French-Canadians) but other
populations and their mutation effects are not fully discussed
4. limited Case Study Analysis
Some mutations are described with case examples, but the number of patient cases is small, making
it hard to generalize conclusions