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- Open Access
Quantitative and qualitative mtDNA-lesions with mitochondrial dysfunction in multiple organs after HAART-associated fatal lactacidosis
© Thoden et al; licensee BioMed Central Ltd. 2008
- Published: 10 November 2008
- Respiratory Chain
- Lactic Acidosis
We describe a 62 year-old HIV-infected male, being treated with didanosine (ddI), stavudine (d4T) and efavirenz, who died with lactacidosis. Co-morbidities were ethanol-induced liver cirrhosis (Child B) and unclear renal insufficiency (GFR 20 ml/min). After 16 months of therapy he developed hyperlactatemia (3.7 mmol/l [normal <2.2]) without acidosis. Two months later after increasing lactic acidosis (pH 6.9, lactate 27 mmol/l) requiring ICU-treatment, including i.v. uridine (20 g/d), he died in multi-organ failure without signs of infection.
Post-mortem, mtDNA copy numbers of the patient's liver, skeletal muscle (SM), heart (HM) and kidney were measured by PCR and compared with nine control autopsies . MtDNA levels were profoundly depleted: liver 7%, kidney 20%, SM 28%, HM 72%. MtDNA of HM and SM were analysed for large scale deletions (8 HM/3 SM) . Sequencing confirmed the DNA fragments to be mitochondrial. Western Blotting of SM and HM proteins showed depressed mtDNA-encoded respiratory chain component COXII in relation to nucleus (nDNA) encoded COXIV. Spectrophotometry revealed reduced activities of COX and NADH dehydrogenase which require an intact mitochondrial genome in both tissues. nDNA encoded activities were preserved. The ultrastructure of both organs showed mitochondrial swelling and small fat vacuoles. The crystal architecture was lost; some organelles were filled with electron dense material.
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