Shirihai 2014 Abstract MiP2014
|Mitochondrial dynamics and quality control, a conflict of interest.|
As our relationship with mitochondria evolves, we remain fascinated by the impact of this organelle in two seemingly unrelated conditions: aging and metabolic diseases. While aging involves insufficiency of mitochondrial quality control and turnover mechanisms (such as autophagy), type II diabetes and obesity are influenced by the ability of the organism to deal with excess nutrient environment. The observation that both conditions are impacted by the duration of exposure to excess nutrient environment raises the question: Are the tasks of handling nutrients in excess and maintaining quality control ever in conflict? Mitochondria go through continuous cycles of selective fusion and fission, referred to as the “mitochondrial life cycle”, to maintain the quality of their function [3-5]. Changes in mitochondrial architecture can represent an adaptation of mitochondria to respire according to the bioenergetic needs of the cell . Conditions requiring high mitochondrial ATP synthesis capacity and/or efficiency, such as limited nutrient availability, are associated with mitochondrial elongation ; reviewed in , while conditions of excess energy supply and relatively low ATP demand, such as beta-cells exposed to excess nutrients, induce mitochondrial fragmentation . This raises the possibility that mitochondrial fragmentation supports uncoupled respiration and thus increases energy expenditure by promoting nutrient oxidation towards heat production, rather than towards mitochondrial ATP synthesis.
To test this hypothesis, we explored a system where a robust shift from coupled to uncoupled respiration and increased energy expenditure can occur. The brown adipocyte offers a unique system where transition to uncoupling can occur within minutes and in a physiological rather than pathological context. Therefore, it represents an attractive model for studying the regulation of energy expenditure induced by hormones.
Our results indicate that norepinephrine induces changes to mitochondrial architecture that serve as an amplification pathway for uncoupling in brown adipocytes. Remarkably, we now have evidence that similar changes, though at a longer time scale, occur in the beta cells under excess nutrient environment. In the beta cell, nutrient–induced fragmentation is associated with increased uncoupling and the enhanced consumption of excess nutrients, thereby serving as an adaptive mechanism.
Placement of bioenergetic adaptation and quality control as competing tasks of mitochondrial dynamics might provide a new mechanism, linking excess nutrient environment to progressive mitochondrial dysfunction, common to age-related diseases.
Labels: MiParea: Respiration, mt-Structure;fission;fusion, Patients Pathology: Aging;senescence, Diabetes, Obesity
Organism: Human Tissue;cell: Fat
Event: A2, Oral MiP2014
Boston Univ School Medicine, MA, USA. - [email protected]
- Gomes LC, Di BG, Scorrano L (2011) During autophagy mitochondria elongate, are spared from degradation and sustain cell viability. Nat Cell Biol 13: 589-98.
- Liesa M, Shirihai OS (2013) Mitochondrial dynamics in the regulation of nutrient utilization and energy expenditure. Cell Metab 17: 491-506.
- Mouli PK, Twig G, Shirihai OS (2009) Frequency and selectivity of mitochondrial fusion are key to its quality maintenance function. Biophys J 96: 3509-18.
- Twig G, Elorza A, Molina AJ, Mohamed H, Wikstrom JD, Walzer G, Stiles L, Haigh SE, Katz S, Las G, Alroy J, Wu M, Py BF, Yuan J, Deeney JT, Corkey BE, Shirihai OS (2008) Fission and selective fusion govern mitochondrial segregation and elimination by autophagy. EMBO J 27: 433-46.
- Twig G, Liu X, Liesa M, Wikstrom JD, Molina AJ, Las G, Yaniv G, Hajnoczky G, Shirihai OS (2010) Biophysical properties of mitochondrial fusion events in pancreatic beta-cells and cardiac cells unravel potential control mechanisms of its selectivity. Am J Physiol Cell Physiol 299: C477-87.
- Wikstrom JD, Katzman SM, Mohamed H, Twig G, Graf SA, Heart E, Molina AJ, Corkey BE, de Vargas LM, Danial NN, Collins S, Shirihai OS (2007) beta-Cell mitochondria exhibit membrane potential heterogeneity that can be altered by stimulatory or toxic fuel levels. Diabetes 56: 2569-78.