Abstract
Mitochondria are dynamic organelles that undergo constant remodeling through the regulation of two opposing processes, mitochondrial fission and fusion. Although several key regulators and physiological stimuli have been identified to control mitochondrial fission and fusion, the role of mitochondrial morphology in the two processes remains to be determined. To address this knowledge gap, we investigated whether morphological features extracted from time-lapse live-cell images of mitochondria could be used to predict mitochondrial fate. That is, we asked if we could predict whether a mitochondrion is likely to participate in a fission or fusion event based on its current shape and local environment. Using live-cell microscopy, image analysis software, and supervised machine learning, we characterized mitochondrial dynamics with single-organelle resolution to identify features of mitochondria that are predictive of fission and fusion events. A random forest (RF) model was trained to correctly classify mitochondria poised for either fission or fusion based on a series of morphological and positional features for each organelle. Of the features we evaluated, mitochondrial perimeter positively correlated with mitochondria about to undergo a fission event. Similarly mitochondrial solidity (compact shape) positively correlated with mitochondria about to undergo a fusion event. Our results indicate that fission and fusion are positively correlated with mitochondrial morphological features; and therefore, mitochondrial fission and fusion may be influenced by the mechanical properties of mitochondrial membranes.
Highlights
Mitochondria regulate a number of cellular processes including cellular metabolism, proliferation, and apoptosis
Recent evidence has shown that mitochondrial morphology is altered by various cellular cues, mitochondrial fission and fusion are active under homeostatic conditions and play important roles in the maintenance of mitochondrial populations [1,2]
The protein availability of the mitochondrial fission and fusion machinery plays an important role in orchestrating the dynamic nature of a particular mitochondrion, we wanted to determine whether the geometric features of mitochondria would play a role in the propensity for mitochondria to fragment or fuse
Summary
Mitochondria regulate a number of cellular processes including cellular metabolism, proliferation, and apoptosis. Maintenance of mitochondrial homeostasis plays a central role in cellular life-death decisions and is regulated, partly, through the competing processes of mitochondrial fission and fusion. A damaged mitochondrion can evade catastrophic failure through fusion with a healthy neighboring mitochondrion. This fusion event allows the mitochondrial population to dilute damage through the mixing of mitochondrial DNA (mtDNA) as well as the exchange of proteins, lipids and small-molecule metabolites [3,4]. A severely damaged mitochondrion may undergo fission to generate smaller mitochondria that are more cleared through a cellular degradation process such as mitophagy [5,6]. Besides maintaining mitochondrial integrity, coordinated changes in mitochondrial morphology have been known to play roles in segregating and protecting mtDNA as well as maintaining electrical and biochemical potentials across the double membrane organelle [8,9]
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