Speaker: Dr. Orian Shirihai, MD Ph.D.
Department of Medicine
Boston University
Boston - USA

HOST

Dr. Antonio Zorzano, IRB Barcelona Monday, 15th March 2010, 15:00 h. Aula Fèlix Serratosa

ABSTRACT

The mitochondrial life cycle consists of frequent fusion and fission events. Ample experimental and clinical data demonstrate that inhibition of either fusion or fission results in deterioration of mitochondrial bioenergetics. While Fusion may benefit mitochondrial function by allowing the spreading of metabolites, protein and DNA throughout the network, the functional benefit of fission is not as intuitive. By tracking individual mitochondria through fusion and fission we found that the two events are paired and that fusion triggers fission. On average each mitochondrion would go though ~5 fusion:fission cycles every hour (see illustration). Measurement of Δψm during individual fusion and fission events showed that fission may yield uneven daughter mitochondria where the depolarized daughter is less likely to become involved in a subsequent fusion and is more likely to be targeted by autophagy.

Based on these observations we propose a mechanism by which the integration of mitochondrial fusion, fission and autophagy forms a quality maintenance mechanism. According to this hypothesis pairs of fusion and fission allow for the reorganization and sequestration of damaged mitochondrial components into daughter mitochondria that are segregated from the networking pool and then becoming eliminated by autophagy. A computerized simulation based on the observed behavior predicts that when paired with fission, fusion events may serve to accelerate the removal of damaged mitochondrial components by autophagy. Therefore the inhibition of either fusion or fission may result in the attenuation of the quality control processes. Furthermore, the simulation predicts the existence of an optimal frequency of fusion and fission events that can maintain respiratory function at steady state levels amid the existence of a continuous damaging process that inactivates mitochondrial components. In the pancreatic beta cell mitochondria bioenergetics play an essential role as a fuel sensor and signal generator for insulin secretion. Accumulation of depolarized mitochondria within beta cells has been associated with oxidative damage and development of diabetes, suggesting a role for mitochondrial quality control mechanisms in the maintenance of beta cell function. Inhibition of mitochondrial dynamics or autophagy in mouse pancreatic beta cells resulted in the accumulation of damaged mitochondrial proteins, mitochondrial dysfunction and impaired insulin secretion. Analysis of mitochondrial fusion and fission proteins in mice showed that diet induced obesity and diabetes are characterized by decreased levels of the mitochondrial fusion protein MFN2. Additionally, long term exposure of beta cells to increased nutrient environment in vitro inhibits mitochondrial fusion and fission dynamics. Remarkably, in vivo deletion of MFN2 in the beta cell in the mouse resulted in the development of severe obesity and diabetes even in the absence of any dietary changes. The ability to beta cell specific deficiency to induce obesity suggests the possibility that nutrient induced obesity might be mediated by the interaction of nutrients with the quality control mechanisms of mitochondria within pancreatic beta cell.

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