Quality Saving Mechanisms of Mitochondria during Aging in a Fully Time-Dependent Computational Biophysical Model

Abstract

Mitochondria are essential for the energy production of eukaryotic cells. During aging mitochondria run through various processes which change their quality in terms of activity, health and metabolic supply. In recent years, many of these processes such as fission and fusion of mitochondria, mitophagy, mitochondrial biogenesis and energy consumption have been subject of research. Based on numerous experimental insights, it was possible to qualify mitochondrial behaviour in computational simulations. Here, we present a new biophysical model based on the approach of Figge et al. in 2012. We introduce exponential decay and growth laws for each mitochondrial process to derive its time-dependent probability during the aging of cells. All mitochondrial processes of the original model are mathematically and biophysically redefined and additional processes are implemented: Mitochondrial fission and fusion is separated into a metabolic outer-membrane part and a protein-related inner-membrane part, a quality-dependent threshold for mitophagy and mitochondrial biogenesis is introduced and processes for activity-dependent internal oxidative stress as well as mitochondrial repair mechanisms are newly included. Our findings reveal a decrease of mitochondrial quality and a fragmentation of the mitochondrial network during aging. Additionally, the model discloses a quality increasing mechanism due to the interplay of the mitophagy and biogenesis cycle and the fission and fusion cycle of mitochondria. It is revealed that decreased mitochondrial repair can be a quality saving process in aged cells. Furthermore, the model finds strategies to sustain the quality of the mitochondrial network in cells with high production rates of reactive oxygen species due to large energy demands. Hence, the model adds new insights to biophysical mechanisms of mitochondrial aging and provides novel understandings of the interdependency of mitochondrial processes.

Fragmentation of the mitochondrial network in skin in vivo

“…The influence of aging processes on mitochondrial quality was investigated in computational quality models. [ 11 , 34 ] A fragmentation of the mitochondrial network during aging of cells and a deceleration of fission and fusion cycles as a quality saving process were observed. The models reveal quality saving mechanisms for mitochondria such as the interplay of mitochondrial networking and recycling and the quality saving benefit of a decreased mitochondrial repair ability in old cells.…”

Mitochondria—A billion years of cohabitation

“…The authors of two PLOS ONE papers set out to model (in very different ways) this complex set of processes to see how useful mitochondrial function can be maintained in an aging body [4] and how day-to-day mitochondrial responses to energetic demands and stress are managed [5]. …”