Unusual mitochondria in the hepatocytes of rats treated with a vitamin B₁₂ analogue

Abstract

Adult male rats were administered hydroxy-cobalamin (c-lactam) (HCCL), a vitamin B12 analogue, by means of osmotic mini-pumps. The metabolic effects of HCCL are similar to those produced by simple dietary deficiency of vitamin B12 (Frenkel et al., 1976), but the morphological alterations in hepatic mitochondria are quite different in the two treatments. In HCCL-treated animals, hepatic mitochondria showed significant increases in number. In one rat, the hepatic mitochondria frequently had a single, elongated, circumferentially-oriented crista, with the inner compartment being occupied by a greatly augmented matrix. Such organelles appeared to be capable of division, as indicated by medially-partitioned forms. Numerous hooded mitochondria were present in the hepatic cells of the same animal. Almost every mitochondrion of whatever morphology was partially or completely shrouded by a cistern of rough endoplasmic reticulum. These mitochondrial morphological changes may be related to the chronic metabolic changes in this animal model of methylmalonic aciduria.

Mitochondrial dysfunction inmutmethylmalonic acidemia

“…This biochemical pattern resembles that seen in hepatic mitochondria from hydroxycobalamin[c-lactam]-treated rats (22), chemical models of methylmalonic acidemia, where the activities of ubiquinol:ferricytochrome c oxidoreductase (complex III) and ferrocytochrome c :oxygen oxidoreductase (complex IV) were markedly reduced after 5 wk of continuous infusion with the inhibitor. In addition, electron microscopy of the liver from such a treated rat revealed megamitochondria (23). Despite the different mechanisms used to produce methylmalonic acidemia in these rodent models (chemical inhibitor vs. genetic), the RC impairment is consistent and supports the hypothesis that the morphologically abnormal mitochondria seen in the Mut Ϫ/Ϫ hepatocytes harbor a functional oxidative phosphorylation defect, which will need to be further examined with respiratory measurements of O 2 consumption and ATP production.…”

Impaired mitochondrial function in HepG2 cells treated with hydroxy-cobalamin[c-lactam]: A cell model for idiosyncratic toxicity

“…In our transmission electron microscopy pictures, we observed a remarkable size variability of mitochondria and mitochondrial swelling after exposure to M a n u s c r i p t 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 18 morphology have been described in rats treated with HCCL (Tandler et al 1991) and also in liver mitochondria of patients with methylmalonic aciduria (Wilnai et al 2014). …”

Translation rates of isolated liver mitochondria under conditions of hepatic mitochondrial proliferation

“…Administration of the hypolipidaemic drug clofibrate is associated with increased contents of liver mitochondria and peroxisomes, via, unknown mechanisms [15]. Recently we have described hepatic niitochondrial proliferation in an animal model of methylmalonic aciduria induced by administration of the cobalamin analogue hydroxycobalamin[c-lactam] (HCCL) [16,17]. Translation rates were quantified in liver mitochondria isolated from control, clofibrate-and HCCL-treated rats to determine if the treatments modified mitochondrial protein expression.…”