Mitochondria: In Sickness and in Health

The mitochondrion is at the core of cellular energy metabolism, being the site of most ATP generation. Calcium is a key regulator of mitochondrial function and acts at several levels within the organelle to stimulate ATP synthesis. However, the dysregulation of mitochondrial Ca(2+) homeostasis is now recognized to play a key role in several pathologies. For example, mitochondrial matrix Ca(2+) overload can lead to enhanced generation of reactive oxygen species, triggering of the permeability transition pore, and cytochrome c release, leading to apoptosis. Despite progress regarding the independent roles of both Ca(2+) and mitochondrial dysfunction in disease, the molecular mechanisms by which Ca(2+) can elicit mitochondrial dysfunction remain elusive. This review highlights the delicate balance between the positive and negative effects of Ca(2+) and the signaling events that perturb this balance. Overall, a "two-hit" hypothesis is developed, in which Ca(2+) plus another pathological stimulus can bring about mitochondrial dysfunction.

https://www.physiology.org/doi/pdf/10.1152/ajpcell.00139.2004

Calcium, ATP, and ROS: a mitochondrial love-hate triangle

Mitochondria: Dynamic Organelles in Disease, Aging, and Development

http://www.somosbacteriasyvirus.com/powerhouse.pdf

Mitochondria: more than just a powerhouse.

Mitochondria are dynamic organelles that constantly fuse and divide. These processes (collectively termed mitochondrial dynamics) are important for mitochondrial inheritance and for the maintenance of mitochondrial functions. The core components of the evolutionarily conserved fusion and fission machineries have now been identified, and mechanistic studies have revealed the first secrets of the complex processes that govern fusion and fission of a double membrane-bound organelle. Mitochondrial dynamics was recently recognized as an important constituent of cellular quality control. Defects have detrimental consequences on bioenergetic supply and contribute to the pathogenesis of neurodegenerative diseases. These findings open exciting new directions to explore mitochondrial biology.

http://fulltext.calis.edu.cn/nature/nrm/11/12/nrm3013.pdf

Mitochondrial fusion and fission in cell life and death

Autosomal dominant optic atrophy (ADOA) is the most prevalent hereditary optic neuropathy resulting in progressive loss of visual acuity, centrocoecal scotoma and bilateral temporal atrophy of the optic nerve with an onset within the first two decades of life. The predominant locus for this disorder (OPA1; MIM 165500) has been mapped to a 1.4-cM interval on chromosome 3q28-q29 flanked by markers D3S3669 and D3S3562 (ref. 3). We established a PAC contig covering the entire OPA1 candidate region of approximately 1 Mb and a sequence skimming approach allowed us to identify a gene encoding a polypeptide of 960 amino acids with homology to dynamin-related GTPases. The gene comprises 28 coding exons and spans more than 40 kb of genomic sequence. Upon sequence analysis, we identified mutations in seven independent families with ADOA. The mutations include missense and nonsense alterations, deletions and insertions, which all segregate with the disease in these families. Because most mutations probably represent null alleles, dominant inheritance of the disease may result from haploinsufficiency of OPA1. OPA1 is widely expressed and is most abundant in the retina. The presence of consensus signal peptide sequences suggests that the product of the gene OPA1 is targeted to mitochondria and may exert its function in mitochondrial biogenesis and stabilization of mitochondrial membrane integrity.

OPA1, encoding a dynamin-related GTPase, is mutated in autosomal dominant optic atrophy linked to chromosome 3q28.

We and others have shown recently that mutations in the OPA1 gene encoding a dynamin-related mitochondrial protein cause autosomal dominant optic atrophy (ADOA) linked to chromosome 3q28-q29. Here we report screening of the OPA1 gene in a sample of 78 independent ADOA families. OPA1 mutations were identified in 25 patients (detection rate 32.1%) including 16 novel mutations. We successfully amplified OPA1 cDNA prepared from leukocyte RNA of three patients, and found the amount of transcripts harboring the Arg366Stop mutation was significantly reduced compared with transcripts derived from the normal chromosome. Analysis of the distribution of OPA1 mutations in ADOA revealed that most missense mutations cluster within the putative GTPase domain, and that there is a preponderance of mutations, which result in premature translation termination. These observations support the notion that haploinsufficiency may represent a major pathomechanism for ADOA. In addition, we identified an ADOA patient who is a compound heterozygote for two OPA1 missense mutations. The fact that this patient is by far more severely affected than her simple heterozygotic parents and siblings implies that at least these OPA1 alleles behave semi-dominantly rather than purely dominantly. Clinical examination revealed considerable variability in disease expression among patients carrying OPA1 mutations and no strict correlation with either the position or the type of mutation.

/pdf/opa1-mutations-in-patients-with-autosomal-dominant-optic-rrm3y2s319.pdf

OPA1 mutations in patients with autosomal dominant optic atrophy and evidence for semi-dominant inheritance.

PURPOSE. Autosomal dominant optic atrophy is a hereditary disorder characterized by progressive loss of vision and caused by mutations in a dynamin-related gene, OPA1, which translates into a protein with a mitochondrial leader sequence. In this study the OPA1 gene and its protein were localized in the rat and mouse retina, and its rat orthologue, rOpa1, was identified. METHODS. The rOpa1 cDNA was isolated by using reverse transcribed cDNA from total RNA obtained from a rat retinal ganglion cell line. The spatial and temporal expression patterns of OPA1 and its gene product were investigated by RNA in situ hybridization and immunohistochemistry in mouse and rat retinas. To characterize further the OPA1-positive neurons, retinal ganglion cells were retrogradely labeled by an immunogold fluorescent tracer or double labeled with OPA1 and choline acetyltransferase or calbindin antibodies. RESULTS. Protein sequence alignment revealed a 96% identity between rat and human OPA1 mRNA. OPA1 expression was found as early as postnatal day 3 in the developing rodent retina. In the mature retina, the OPA1 gene and its protein were found not only in retinal ganglion cells, but also in starburst amacrine cells and horizontal cells, both of which are involved in lateral signal processing within the retina. However, OPA1 was absent from mitochondria rich nerve fibers and photoreceptor indicating a specific role for OPA1 in signal processing rather than in the requirement of mitochondrial energy supply in the retina. CONCLUSIONS. The data suggest an important and specific function of the OPA1 protein, not only in the optic nerve forming ganglion cells but also in the intrinsic signal processing of the inner retina. (Invest Ophthalmol Vis Sci. 2004;45:4217‐4225)

/pdf/opa1-the-disease-gene-for-autosomal-dominant-optic-atrophy-4ghd9h371x.pdf

Ulrike E.A. Pesch

Papers

OPA1, encoding a dynamin-related GTPase, is mutated in autosomal dominant optic atrophy linked to chromosome 3q28.

OPA1 mutations in patients with autosomal dominant optic atrophy and evidence for semi-dominant inheritance.

OPA1, the disease gene for autosomal dominant optic atrophy, is specifically expressed in ganglion cells and intrinsic neurons of the retina.

OPA1, encoding a dynamin-related GTPase is mutated in autosomal dominant optic atrophy linked to chromosome 3q28