[Diseases caused by mutations in mitochondrial DNA].
ABSTRACT Mitochondrial diseases associated with mutations within mitochondrial genome are a subgroup of metabolic disorders since their common consequence is reduced metabolic efficiency caused by impaired oxidative phophorylation and shortage of ATP. Although the vast majority of mitochondrial proteins (approximately 1500) is encoded by nuclear genome, mtDNA encodes 11 subunits of respiratory chain complexes, 2 subunits of ATP synthase, 22 tRNAs and 2 rRNAs. Up to now, more than 250 pathogenic mutations have been described within mtDNA. The most common are point mutations in genes encoding mitochondrial tRNAs such as 3243A-->G and 8344T-->G that cause, respectively, MELAS (mitochondrial encephalopathy, lactic acidosis and stroke-like episodes) or MIDD (maternally-inherited diabetes and deafness) and MERRF (myoclonic epilepsy with ragged red fibres) syndromes. There have been also found mutations in genes encoding subunits of ATP synthase such as 8993T-->G substitution associated with NARP (neuropathy, ataxia and retinitis pigmentosa) syndrome. It is worth to note that mitochondrial dysfunction can also be caused by mutations within nuclear genes coding for mitochondrial proteins.
- SourceAvailable from: Hang Fang[show abstract] [hide abstract]
ABSTRACT: Mitochondria are not only the main energy generators of the cell, but also mediate several critical biochemical processes such as apoptosis, proliferation and redox homeostasis. As such, mitochondrial dysfunctions can lead to a wide variety of human diseases, including cancer and osteoarthritis (OA). In OA, mitochondrial-associated signaling has been implicated in the molecular events leading to cartilage degradation, including oxidative stress, defective chondrocyte biosynthesis and growth responses, increased cytokine-induced chondrocyte inflammation and matrix catabolism, cartilage matrix calcification and increased chondrocyte apoptosis. Thus, the mitochondrial genome represents an attractive target for molecular therapy and OA research has focused on determining its role in chondrocyte metabolism and subsequent cartilage degradation. In this study, we analyzed the mitochondrial gene expression changes that characterize chondrocytes in OA using the Human Mitochondria RT² Profiler™ PCR Array. Twenty-six differentially expressed genes were identified that discriminated chondrocytes in OA from those in normal cartilage, including 17 upregulated and 9 downregulated genes. These genes represent diverse functional categories, including mitochondrial membrane polarization and potential, mitochondrial transport, small molecule transport, targeting proteins to the mitochondria, mitochondrial protein import, outer and inner membrane translocation, mitochondrial fission and fusion, mitochondrial localization and apoptosis. Western blot analysis confirmed that the p53 upregulated modulator of apoptosis (PUMA; encoded by the BB3 gene) was significantly upregulated in OA cartilage. In conclusion, our study generates a differential mitochondrial gene expression profile for chondrocytes in OA and demonstrates that mitochondrial genome dysregulation occurs in cartilage cells during OA. Finally, our results indicate that PUMA may be a new diagnostic and therapeutic target for OA.Molecular Medicine Reports 04/2012; 6(1):39-44. · 1.17 Impact Factor