A 42-year-old man with a history of tuberculosis treated with rifampicin and isoniazid 2 years ago now presents with progressive weakness, tremor, and cognitive decline. Brain MRI shows basal ganglia calcification. Serum lactate is 5.2 mmol/L (normal <2). Muscle biopsy reveals ragged-red fibres. Genetic analysis identifies a heteroplasmic m.3243A>G mutation in the MT-TL1 gene (mitochondrial tRNA^Leu^). Which electron transport chain complex is MOST likely to be functionally impaired in this patient?

Explanation

## m.3243A>G Mutation and Mitochondrial Translation Defect ### The Mutation: MT-TL1 Gene **Key Point:** The m.3243A>G mutation is the most common pathogenic mitochondrial DNA variant worldwide. It affects the **mitochondrial tRNA^Leu(UUR)^** gene (MT-TL1), which is essential for decoding UUA and UUG leucine codons during mitochondrial translation. **High-Yield:** This mutation causes **MELAS syndrome** (Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like Episodes) — the classic triad seen in this patient (cognitive decline, lactic acidosis, basal ganglia lesions, ragged-red fibres). --- ### Which Complex Is Most Affected? **Clinical Pearl:** Although the m.3243A>G mutation broadly impairs mitochondrial translation (affecting all 13 mitochondrially-encoded proteins), **Complex I and Complex IV** are most severely affected in practice. The question asks which is **MOST likely** impaired, and the answer is **Complex IV (cytochrome c oxidase)** based on the following mechanistic reasoning: #### Why Complex IV (Option B)? 1. **COX subunits 1, 2, and 3 (COX1, COX2, COX3)** are mitochondrially encoded and are among the most leucine-rich of all 13 mtDNA-encoded proteins 2. **Defective tRNA^Leu^** → impaired decoding of UUA/UUG codons → stalled or misfolded COX subunits 3. **COX assembly failure** → reduced electron transfer from cytochrome c to O₂ → bioenergetic collapse 4. Multiple biochemical studies (Chomyn et al.; Rossignol et al.) confirm **Complex IV deficiency** as the predominant enzymatic defect in MELAS cybrid cell lines carrying m.3243A>G > **Note on Complex I:** While Complex I activity is also reduced in some MELAS patients (due to the global translation impairment), it is **not the primary or most selective target** of the m.3243A>G mutation. Complex I deficiency is more classically associated with Leigh syndrome (mutations in ND subunit genes or SURF1/SDHA assembly factors), not MELAS. --- ### Why the Other Options Are Wrong | Option | Why Incorrect | |--------|--------------| | **A – Complex I / isoniazid** | Isoniazid causes peripheral neuropathy via pyridoxine depletion; it does **not** selectively impair Complex I. The patient's ETC defect is genetic, not drug-induced. | | **C – Complex II / SDH mutation** | Complex II (succinate dehydrogenase) is **entirely nuclear-encoded**; it is unaffected by mitochondrial tRNA mutations. SDH mutations cause paraganglioma/pheochromocytoma, not MELAS. | | **D – Complex III** | Complex III (cytochrome bc1) contains only one mtDNA-encoded subunit (cytochrome b). While theoretically affected by tRNA^Leu^ dysfunction, it is **not the predominant** complex impaired in m.3243A>G MELAS. | --- ### Clinical Correlation - **Ragged-red fibres** → mitochondrial proliferation (subsarcolemmal accumulation) compensating for energy deficit — classic on Gomori trichrome stain - **Lactic acidosis (lactate 5.2 mmol/L)** → impaired oxidative phosphorylation → pyruvate shunted to lactate - **Basal ganglia calcification** → stroke-like lesions from mitochondrial angiopathy and neuronal energy failure - **Heteroplasmy** → mixture of mutant and wild-type mtDNA explains variable tissue involvement and progressive phenotype **Mnemonic:** **MELAS = Mitochondrial tRNA^Leu^ → ETC failure (Complex IV) → Lactic Acidosis + Stroke-like episodes** *(Reference: DiMauro S & Schon EA, NEJM 2003; Chomyn A et al., PNAS 1992; Harrison's Principles of Internal Medicine, 21st ed., Chapter on Mitochondrial Disease)*