Lipomatosis, proximal myopathy, and the mitochondrial 8344 mutation. A lipid storage myopathy?

Mitochondrial dysfunction induces triglyceride accumulation in 3T3-L1 cells: role of fatty acid β-oxidation and glucose

“…** Significantly different from control cells at P Ͻ 0.01. activity of some transcription factors (34), a phenomenon initially observed in yeast (35) and more recently in mammalian cells (11,36). Here, we studied the response of 3T3-L1 preadipocytes to mitochondrial dysfunction, a condition that has previously been associated with an atypical adipocyte phenotype (7) observed in pathologies characterized by dyslipidemia or lipodystrophy (2). To address the mechanisms by which mitochondrial dysfunction can lead to an increase in cytosolic TG content, 3T3-L1 preadipocytes were subjected to a prolonged mitochondrial activity inhibition induced by inhibitors of oxidative phosphorylation.…”

“…Indeed, chronic mitochondrial dysfunction can lead to diseases characterized by lipid metabolism disorders and pathological triglyceride (TG) accumulation in several cell types (1)(2)(3). Genetic mitochondrial pathologies usually result from point mutations or deletions in mitochondrial DNA that finally impair oxidative phosphorylation capacity (4).…”

“…Interestingly, some mitochondrial disorders affect lipid-metabolizing tissues such as muscular and adipose tissues. For example, the myoclonic epilepsy with ragged red fibers (MERRF) syndrome, commonly caused by a point mutation in the mitochondrial tRNA Lys -encoding gene (A8344G), is associated with myopathy, TG accumulation in muscles (5), and, in some cases, multiple symmetrical lipomatosis (MSL) (2,6). MSL is a pathology characterized by the formation of lipomas containing abnormal white adipocytes smaller than normal adipocytes showing a multivesicular phenotype (1,2,7).…”

“…For example, the myoclonic epilepsy with ragged red fibers (MERRF) syndrome, commonly caused by a point mutation in the mitochondrial tRNA Lys -encoding gene (A8344G), is associated with myopathy, TG accumulation in muscles (5), and, in some cases, multiple symmetrical lipomatosis (MSL) (2,6). MSL is a pathology characterized by the formation of lipomas containing abnormal white adipocytes smaller than normal adipocytes showing a multivesicular phenotype (1,2,7). Moreover, biochemical analyses have shown that cytochrome c oxidase activity is impaired in muscles from patients with MSL (8), supporting the fact that the disease is linked to mitochondrial dysfunction (6,9).…”

CREB activation induced by mitochondrial dysfunction triggers triglyceride accumulation in 3T3-L1 preadipocytes

“…It has also been shown that most of multiple symmetrical lipomatosis (MSL) patients also display mitochondrial dysfunction Berkovic et al, 1991), lipomas that contain atypical multivacuolar white adipocytes (Zancanaro et al, 1990) as well as ragged red fibers and TG accumulation in muscles (Klopstock et al, 1997;Munoz-Malaga et al, 2000). The role of mitochondria in TG metabolism is also strengthened by their implication in the lipodystrophy syndrome resulting from antiretroviral therapies that combine drugs known to inhibit mitochondrial DNA polymerase ␥ and mitochondrial processing protease (Kakuda, 2000;Brinkman et al, 1999).…”