Mitochondrial chaos: Redox-energetic behavior at the edge

SOLLOTT, STEVEN J.; CORTASSA, SONIA; KEMBRO, J. M.; AON, MIGUEL A.

San Fransisco

Encuentro; 62th Annual meeting of the Biophysical Society; 2018

Biophysical Society

Mitochondria serve a multiplicity of key cellular functions, including energy generation, regulation of redox balance, thus making a major impact on healthy and diseased states. Collectively, mitochondrial dynamics contribute directly or indirectly to regulate the level of key metabolites (e.g., NAD+, acetyl CoA, ATP, S-adenosyl methionine) at the cross-roads of epigenome-genome-metabolic functional interactions arising from nutritional status and lifestyle decisions. It is increasingly recognized that biological network stability/instability can play critical roles in determining health and disease. Herein, we investigate and characterize the conditions leading from stability to mitochondrial chaotic dynamics. Using an experimentally validated bi-compartmental computational model of mitochondrial function, we show that complex oscillatory dynamics in key metabolic variables, arising at the ?edge? between fully functional and pathological behavior, sets the stage for chaotic dynamics. Under those conditions, a mild, regular sinusoidal redox perturbation, such as occurs naturally during each heartbeat, triggers chaotic dynamics with main signature traits such as sensitivity to initial conditions, positive dominant Lyapunov exponents, and strange attractors. The transition to mitochondrial chaos is exquisitely sensitive to the matrix SOD2 antioxidant capacity as well as to the amplitude and frequency of the extra-mitochondrial redox perturbation, shifting between low- (limit cycles without or with period doubling) and high-dimensional dynamic regimens (complex oscillations, chaos). Overall, this work describes the conditions leading to mitochondrial chaotic dynamics and their potential implications both for homeostatic mitochondrial signaling determining health maintenance, and for pathological transformation, including abnormal cardiac rhythms.