دانلود رایگان مقاله انگلیسی یک چشم انداز جدی درباره استرس: تمرکزی بر میتوکندری - الزویر 2018

ABSTRACT

Energy is required to sustain life and enable stress adaptation. At the cellular level, energy is largely derived from mitochondria – unique multifunctional organelles with their own genome. Four main elements connect mitochondria to stress: (1) Energy is required at the molecular, (epi)genetic, cellular, organellar, and systemic levels to sustain components of stress responses; (2) Glucocorticoids and other steroid hormones are produced and metabolized by mitochondria; (3) Reciprocally, mitochondria respond to neuroendocrine and metabolic stress mediators; and (4) Experimentally manipulating mitochondrial functions alters physiological and behavioral responses to psychological stress. Thus, mitochondria are endocrine organelles that provide both the energy and signals that enable and direct stress adaptation. Neural circuits regulating social behavior – as well as psychopathological processes – are also influenced by mitochondrial energetics. An integrative view of stress as an energy-driven process opens new opportunities to study mechanisms of adaptation and regulation across the lifespan.

15. Conclusions section

Mitochondria were essential to the development of complex multicellular life forms, and only recently have we started to develop a scientific understanding of the interplay between specific aspects of mitochondrial biology and stress responses. The mechanistic pre-clinical findings reviewed above provide converging evidence that mitochondrial energetics may directly impact neuroendocrine and metabolic responses to psychological stress, epigenetic regulation within the brain, food and energy seeking behaviors, psychological states such as depression, and complex social behaviors. It will be a fascinating challenge for behavioral neuroscientists to determine whether mitochondrial energy production capacity or other mitochondrial signals influence psychological states and social behaviors in humans also, and if so, whether interventions targeted at mitochondria can influence complex behaviors and promote adaptation and health.

Much attention in the past decades has been devoted to mapping the contribution of specific anatomical structures within and outside the brain to the stress response, including neuroendocrine mediators and the immune system. The brain has been regarded as a central organ of adaptation (McEwen, 2006). The work reviewed above implicates mitochondria as a central organelle of adaptation, operating at multiple levels within the stress response cascade. Via their effects on neuroendocrine mechanisms, mitochondria drive adaptive signaling processes and behaviors. Simultaneously, mitochondria sense changes in energy demand, and rapidly respond – in shape and function – to energy-mobilizing glucocorticoids and catecholamine hormones. It is enlightening to consider that evolution has routed the production of glucocorticoids and sex hormones within the mitochondria of specialized steroid-secreting cells (adrenal cortex, gonads). In turn, mitochondria in other tissues like the brain, muscles, and liver sense and functionally respond to glucocorticoids via the action of GR and other “nuclear” receptors on the mtDNA. Mitochondria are both mediators and targets of the main stress axes. Therefore, glucocorticoids should be regarded as mitochondria-derived hormones, or mitokines mediating mitochondria-to-mitochondria communication among distant sites throughout the organism. Much remains to be discovered about the mechanisms and implications of mitocrine signaling.