A data-driven model for mitochondrial inner membrane remodeling as a driving force of organelle shaping

Mitochondria are dynamic organelles exhibiting diverse shapes. Although variation in mitochondrial shapes, which range from spheres to elongated tubules, and the transitions between them are clearly seen in many cell types, the molecular mechanisms governing this morphological variability remain poorly understood. Here, we propose a biophysical model for the shape transition between spheres and tubules based on the interplay between the inner and outer mitochondrial membranes. Our model suggests that the difference in surface area, arising from folding of the inner membrane into cristae, correlates with mitochondrial elongation. Analysis of live-cell super-resolution microscopy data supports this correlation, linking elongated shapes to the extent of cristae in the inner membrane. Knocking down cristae-shaping proteins further confirms the impact on mitochondrial shape, demonstrating that defects in cristae formation correlate with mitochondrial sphericity. Our results suggest that the dynamics of the inner mitochondrial membrane are not only important for simply creating surface area required for respiratory capacity but go beyond that to affect the whole organelle morphology. This work explores the biophysical foundations that govern the shape of individual mitochondria, suggesting potential links between mitochondrial structure and function. This should be of profound significance, particularly in the context of disrupted cristae-shaping proteins and their implications in mitochondrial diseases.