A 25-year-old woman with sensorineural hearing loss, ptosis, and proximal muscle weakness has ragged-red fibers on muscle biopsy. Genetic testing reveals a large mitochondrial DNA deletion. The ETC complex most sensitive to mitochondrial DNA deletions encoding core subunits would be:

• A Complex II (succinate dehydrogenase), as all four subunits are mitochondrially encoded
• B Complex I only, as it has the largest number of total subunits
• C Complexes I, III, IV, and V, as their catalytic core subunits are encoded by mtDNA ✓
• D ATP synthase (Complex V) exclusively, as the proton channel relies entirely on mtDNA-encoded subunits

Explanation

The mitochondrial genome encodes 13 proteins, all of which are subunits of the OXPHOS complexes: 7 subunits of Complex I (ND1-ND6, ND4L), 1 subunit of Complex III (Cytochrome b), 3 subunits of Complex IV (COX1-3), and 2 subunits of ATP synthase (ATP6, ATP8). Crucially, Complex II (succinate dehydrogenase) is entirely encoded by nuclear DNA, making it resistant to mtDNA mutations. Large mtDNA deletions (such as in Kearns-Sayre syndrome or Pearce syndrome) impair multiple complexes simultaneously. The ragged-red fiber pattern on modified Gomori trichrome reflects subsarcolemmal mitochondrial accumulation.

Reference: Harper's Illustrated Biochemistry, 32nd ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.