Mitochondrial Function Reflected by the Decarboxylation of [¹³C]Ketoisocaproate Is Impaired in Alcoholics

Abstract

Mitochondria of patients with alcoholic liver disease exhibit structural abnormalities, and mitochondria isolated from animals exposed to ethanol are functionally deficient when studied in vitro. To assess possible functional consequences of these ethanol-associated alterations in vivo, we measured mitochondrial function in alcoholics noninvasively with a breath test. A mitochondrial function, the decarboxylation of ketoisocaproate (KICA), was assessed by measuring the exhalation of 13CO2 following the administration of 1 mg/kg 2-keto[1-13C]isocaproic acid, the decarboxylation of which occurs in mitochondria. The results of the KICA breath test in 12 alcoholic subjects were compared with the results in healthy controls and patients with nonalcoholic liver disease. The peak exhalation of 13CO2 and the fraction of the administered dose decarboxylated in 120 min were both significantly lower in alcoholics than in healthy controls and patients with nonalcoholic liver disease. In alcoholics, KICA decarboxylation was impaired in the presence of normal quantitative liver function tests such as the aminopyrine breath test and galactose elimination capacity, indicating that KICA decarboxylation does not simply reflect a decreased functional hepatic mass. The enrichment of circulating KICA with [13C]KICA was similar in alcoholics and controls, indicating that a decreased bioavailability or an increased dilution of labeled KICA cannot account for the decreased exhalation of 13CO2. It is concluded that mitochondrial function as reflected by KICA decarboxylation is impaired in chronic alcoholics. The functional impairment is specific for ethanol abuse and not a reflection of decreased global hepatic function. KICA decarboxylation could thus be useful as a marker for excessive ethanol consumption.

Laboratory approach to mitochondrial diseases

“…Our results obtained in healthy men and women are in agreement with previously published results (30,43,56,133). We have not found differences in 2-keto[l-13Clisocaproic acid oxidation due to corporal composition, gender, or branched chain amino acid plasma levels and inter and intrasubject variability have been low.…”

“…The 2-keto[1-14C]isocaproic acid breath test was validated to assess liver mitochondrial function in rats (69). Later, results obtained in experimental animals were tested in humans (56,70) and using the 13C-substrate as a tracer (56,133).…”

Methods and functions: Breath tests

“…Special 13 C-labelled substrates were sought to investigate mitochondrial (methionine [57,58], ketoisocaproic acid [59,60], octanoic acid [61]), cytosolic (galactose [62][63][64]), or microsomal (aminopyrine [57,62,[65][66][67][68][69][70], methacetin [64,[71][72][73][74][75][76], phenylalanine [73], caffeine [67]) enzyme function. Some substrates depend on the liver blood flow (methacetin), others not (aminopyrine [62,68]).…”

Postprandial insulin response and mitochondrial oxidation in obese men nutritionally treated to lose weight

“…The human branched chain 2-keto acid dehydrogenase complex, which modulate the oxidation of 2-keto[1-13 C]isocaprote, is located not only in the liver (Lauterburg et al, 1993;Witschi et al, 1994;Mion et al, 1995) but also in the pancreas, the kidney, the brain, Lean controls Obese with HOMA-index < 3.5 Obese with HOMA-index > 3.5 Figure 3 Percentage of the 2-keto(1-13 C)isocaproate mitochondrially oxidized corrected for body weight obtained at baseline in lean controls and in both obese groups and after the calorie-restriction programme in the participating obese (statistical differences reported if Po0.05).…”