Mechanical force induces mitochondrial fission

Abstract

Eukaryotic cells are densely packed with macromolecular complexes and intertwining organelles, continually transported and reshaped. Intriguingly, organelles avoid clashing and entangling with each other in such limited space. Mitochondria form extensive networks constantly remodeled by fission and fusion. Here, we show that mitochondrial fission is triggered by mechanical forces. Mechano-stimulation of mitochondria – via encounter with motile intracellular pathogens, via external pressure applied by an atomic force microscope, or via cell migration across uneven microsurfaces – results in the recruitment of the mitochondrial fission machinery, and subsequent division. We propose that MFF, owing to affinity for narrow mitochondria, acts as a membrane-bound force sensor to recruit the fission machinery to mechanically strained sites. Thus, mitochondria adapt to the environment by sensing and responding to biomechanical cues. Our findings that mechanical triggers can be coupled to biochemical responses in membrane dynamics may explain how organelles orderly cohabit in the crowded cytoplasm.

Mitochondrial membrane tension governs fission

“…For instance, the existence of multiple Drp1 adaptor proteins is indicative of their complementary roles [24], while Dyn2 has been shown to be a frequent, but non-essential partner in mediating mitochondrial fission [23], suggesting that different combinations of molecular machinery can lead to fission. Furthermore, deformations induced by external mechanical forces can trigger recruitment of the downstream machinery for mitochondrial fission [25]. These observations are consistent with the nature of membrane fission processes as requiring membrane deformation, agnostic of its origins.…”

“…The probabilistic nature of mitochondrial fission and the prevalence of reversals may play a role in regulating global mitochondrial network morphologies. Given the highly crowded intracellular environment, the resulting mechanical forces could recruit the mitochondrial division machinery in an unregulated manner, leading to fragmentation of the network [25]. Our model provides insight into how by modulating tension, the degree of fragmentation might be regulated.…”

ActuAtor, a molecular tool for generating force in living cells: Controlled deformation of intracellular structures

“…Mechanical force regulates diverse biological processes including development (Mammoto et al, 2013), gene expression (Shivashankar, 2019), differentiation (Vining and Mooney, 2017), protein trafficking (Kassianidou et al, 2019), and dynamics of cellular and intracellular architecture including cell division (Itabashi et al, 2013; Elting et al, 2018), directed migration (Diz-Muñoz et al, 2013; Iskratsch et al, 2014) and organelle morphology regulation (Isermann and Lammerding, 2013; Helle et al, 2017). While cells sense and respond to extracellular physical forces mostly at the plasma membrane, recent studies implied active mechonoresponses in the intracellular milieu (Elosegui-Artola et al, 2017; Helle et al, 2017). Deficiencies or changes in cellular mechano-responses have been linked to diseased states including cancer (Ingber, 2003; Suresh, 2007; Isermann and Lammerding, 2013), collectively supporting the physiological importance of these mechanobiological processes.…”

“…In contrast, biological probes such as motile microorganisms and engineered proteins can be introduced into cells with little effort. One example is the use of individual bacteria to apply force onto mitochondria (Helle et al, 2017). This study used pathogenic bacteria Listeria monocytogenes which enter host cells through phagocytosis followed by escape from the phagosome (Radoshevich and Cossart, 2018) ( Supplementary Figure 1a ).…”

Energy Expenditure during Cell Spreading Regulates the Stem Cells Responses to Matrix Stiffness

“…AMPK is a key regulator of mitochondrial dynamics, as it can phosphorylate and thereby activate a mitochondrial fission factor (Mff), which stimulates mitochondrial division 21,22 . Alterations in mitochondrial fission, fusion and morphology are induced by mechanical cues, chemical stimulations or metabolic stresses [22][23][24] . A recent study in MCF10A (human breast epithelial) cells and MDCK II (canine kidney epithelial) cells, revealed that force-mediated AMPK activation stimulated actomyosin contractility and increased cellular ATP levels, thus linking energy homeostasis with cell-cell adhesion mechanotransduction 11 .…”