Mitochondria in Multiple Sclerosis: Molecular Mechanisms of Pathogenesis.

Mitochondria, the organelles that function as the powerhouse of the cell, have been increasingly linked to the pathogenesis of many neurological disorders, including multiple sclerosis (MS). MS is a chronic inflammatory demyelinating disease of the central nervous system (CNS) and a leading cause of neurological disability in young adults in the western world. Its etiology remains unknown, and while the inflammatory component of MS has been heavily investigated and targeted for therapeutic intervention, the failure of remyelination and the process of axonal degeneration are still poorly understood. Recent studies suggest a role of mitochondrial dysfunction in the neurodegenerative aspects of MS. This review is focused on mitochondrial functions under physiological conditions and the consequences of mitochondrial alterations in various CNS disorders. Moreover, we summarize recent findings linking mitochondrial dysfunction to MS and discuss novel therapeutic strategies targeting mitochondria-related pathways as well as emerging experimental approaches for modeling mitochondrial disease.

Identification of PTEN at the ER and MAMs and its regulation of Ca(2+) signaling and apoptosis in a protein phosphatase-dependent manner.

The tumor suppressor activity of PTEN (phosphatase and tensin homolog deleted on chromosome 10) is thought to be largely attributable to its lipid phosphatase activity. PTEN dephosphorylates the lipid second messenger phosphatidylinositol 3,4,5-trisphosphate to directly antagonize the phosphoinositide 3-kinase-Akt pathway and prevent the activating phosphorylation of Akt. PTEN has also other proposed mechanisms of action, including a poorly characterized protein phosphatase activity, protein-protein interactions, as well as emerging functions in different compartment of the cells such as nucleus and mitochondria. We show here that a fraction of PTEN protein localizes to the endoplasmic reticulum (ER) and mitochondria-associated membranes (MAMs), signaling domains involved in calcium ((2+)) transfer from the ER to mitochondria and apoptosis induction. We demonstrate that PTEN silencing impairs ER Ca(2+) release, lowers cytosolic and mitochondrial Ca(2+) transients and decreases cellular sensitivity to Ca(2+)-mediated apoptotic stimulation. Specific targeting of PTEN to the ER is sufficient to enhance ER-to-mitochondria Ca(2+) transfer and sensitivity to apoptosis. PTEN localization at the ER is further increased during Ca(2+)-dependent apoptosis induction. Importantly, PTEN interacts with the inositol 1,4,5-trisphosphate receptors (IP3Rs) and this correlates with the reduction in their phosphorylation and increased Ca(2+) release. We propose that ER-localized PTEN regulates Ca(2+) release from the ER in a protein phosphatase-dependent manner that counteracts Akt-mediated reduction in Ca(2+) release via IP3Rs. These findings provide new insights into the mechanisms and the extent of PTEN tumor-suppressive functions, highlighting new potential strategies for therapeutic intervention.

Laparoscopic myomectomy for fibroids penetrating the uterine cavity: is it a safe procedure?

OBJECTIVE: The purpose of the study was to evaluate the post-operative course and follow up of women who had undergone laparoscopic removal of intramural fibroids penetrating the uterine cavity. DESIGN: Retrospective study. SETTING: Center for Reconstructive Pelvic Endosurgery, Italy. POPULATION: Thirty-four women with fibroids penetrating the uterine cavity. METHODS: Laparoscopic myomectomy. MAIN OUTCOME MEASURES: Feasibility and safety of surgical technique, length of operation, blood loss, intra- or post-operative complications, length of hospital stay, resolution of symptoms and future obstetric outcome. RESULTS: The mean operative time was 79 (SD 30) minutes; the mean reduction in haemoglobin was 1.1 +/- 0.9 g/dL. No intra- or post-operative complications were observed. The average post-operative stay in hospital was 54 (SD 22) hours. Nineteen (73%) out of 26 patients who had experienced symptoms prior to surgery reported resolution of these symptoms post-operatively. All patients resumed work within a mean time of 20 (SD 8) days. Among 23 of the 32 patients attempting pregnancy during the follow up period, nine (39%) conceived within one year. Seven pregnancies went to term without complications. CONCLUSIONS: The clinical results of this study suggest that laparoscopic myomectomy for intramural fibroids penetrating the uterine cavity is a safe procedure, providing well known advantages of minimal access surgery.

Fertility and tumor recurrence rate after conservative laparoscopic management of young women with early-stage borderline ovarian tumors.

OBJECTIVE: To evaluate the efficacy of laparoscopic conservative surgery in young women with borderline ovarian tumors who want to preserve their childbearing potential, and to assess whether pregnancy influences the recurrence rate during the follow-up evaluation period. DESIGN: Retrospective study. SETTING: Center for Reconstructive Pelvic Endosurgery, Reproductive Medicine Unit, S. Orsola Hospital, University of Bologna, Italy. PATIENT(S): Nineteen women (mean age 27.4 +/- 4.7) with borderline ovarian tumors who underwent laparoscopy between January 1995 and January 1998. All of the women wanted to preserve their fertility. INTERVENTION(S): A standardized conservative laparoscopic approach and a strict follow-up schedule. MAIN OUTCOME MEASURE(S): A complete preoperative examination. RESULT(S): Follow-up evaluations (mean 42 +/- 19 months) were made available to all patients. Among 19 patients, 10 attempted pregnancy and 6 conceived spontaneously. All six pregnancies went to term and the disease did not affect the gestation or the follow-up period after the pregnancy (24.5 +/- 15.7 months). CONCLUSION(S): Conservative laparoscopic management of borderline ovarian tumors is a potentially safe alternative in young women who want to retain their childbearing potential. Fertility and pregnancy outcome remain excellent in these women. Our preliminary data seem to indicate that the recurrence rate after pregnancy is not influenced by this approach.

Conservative treatment of recurrent ovarian fibromas in a young patient affected by Gorlin syndrome.

The case of recurrent bilateral ovarian fibromas occurring in a 22 year old Italian girl affected by Gorlin syndrome is reported. Ovarian fibromas occur in 75% of female patients with Gorlin syndrome and their recurrence has rarely been reported in the literature. Management is guided by the benign nature of the lesion and consists of surgical removal of the fibroma. Preservation of the normal ovarian tissue is recommended even though there is risk of recurrence of the fibroma.