Abstract

Mitochondrial cristae are dynamic invaginations of the inner membrane and play a key role in its metabolic capacity to produce ATP. Structural alterations caused by either genetic abnormalities or detrimental environmental factors impede mitochondrial metabolic fluxes and lead to a decrease in their ability to meet metabolic energy requirements. While some of the key proteins associated with mitochondrial cristae are known, very little is known about how the inner membrane dynamics are involved in energy metabolism. In this study, we present a computational strategy to understand how cristae are formed using a phase-based separation approach of both the inner membrane space and matrix space, which are explicitly modeled using the Cahn–Hilliard equation. We show that cristae are formed as a consequence of minimizing an energy function associated with phase interactions which are subject to geometric boundary constraints. We then extended the model to explore how the presence of calcium phosphate granules, entities that form in calcium overload conditions, exert a devastating inner membrane remodeling response that reduces the capacity for mitochondria to produce ATP. This modeling approach can be extended to include arbitrary geometrical constraints, the spatial heterogeneity of enzymes, and electrostatic effects to mechanize the impact of ultrastructural changes on energy metabolism.

Highlights

  • Introduction published maps and institutional affilMitochondria are small organelles that provide the bulk of the energy requirements for most cells in most eukaryotic organisms

  • Our data show that a calcium overload causes significant remodeling of the inner membrane, which likely explains the decrease in mitochondrial respiration

  • We modeled the mitochondrial ultrastructural remodeling caused by calcium phosphate granules by using a volume exclusion approach in the CH model. By using this phase separation-based modeling approach, we show that the presence of calcium phosphate granules exerts a devastating remodeling effect on the inner membrane, which results in matrix expansion, intermembrane space (IMS) contraction, and cristae remodeling

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Summary

Introduction

Introduction published maps and institutional affilMitochondria are small organelles that provide the bulk of the energy requirements for most cells in most eukaryotic organisms. A few modeling studies have explored the potential role of mitochondrial proteins in the inner membrane architecture and metabolic function [45,46,47,48,49,50,51,52,53,54]. Our data show that a calcium overload causes significant remodeling of the inner membrane, which likely explains the decrease in mitochondrial respiration.

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