Preprint Matrix stiffening promotes perinuclear clustering of mitochondria, 2023, Daga et al.

[SNT Gatchaman]

Matrix stiffening promotes perinuclear clustering of mitochondria
Piyush Daga; Basil Thurakkal; Simran Rawal; Tamal Das

Mechanical cues from the tissue microenvironment, such as the stiffness of the extracellular matrix, modulate cellular forms and functions. As numerous studies have shown, this modulation depends on the stiffness-dependent remodeling of cytoskeletal elements. In contrast, very little is known about how the intracellular organelles such as mitochondria respond to matrix stiffness and whether their form, function, and localization change accordingly.

Here, we performed an extensive quantitative characterization of mitochondrial morphology, subcellular localization, dynamics and membrane tension on soft and stiff matrices. This characterization revealed that while matrix stiffness affected all these aspects, matrix stiffening most distinctively led to an increased perinuclear clustering of mitochondria. Subsequently, we could identify the matrix stiffness-sensitive perinuclear localization of filamin as the key factor dictating this perinuclear clustering. Photo-conversion labeling and fluorescent recovery after photobleaching experiments revealed that perinuclear and peripheral mitochondrial populations differed in their motility on the soft matrix but surprisingly they did not show any difference on the stiff matrix. Finally, perinuclear mitochondrial clustering appeared to be crucial for priming human mesenchymal stem cells towards osteogenesis on the stiff matrix.

Taken together, we elucidate a dependence of mitochondrial localization on matrix stiffness, which possibly enables a cell to adapt to its microenvironment.

Link | PDF (Preprint: BioRxiv)

 

[SNT Gatchaman]

The cells in our body constantly change their internal organization and adapt to various signals emanating from the extracellular environment. Mechanical cues from the extracellular matrix (ECM) elicit an intracellular tensional response that ensures tissue homeostasis. This response manifests itself in terms of cytoskeletal remodeling, altering actomyosin contractility, driving nuclear reprogramming, and metabolic adaptations.

in the context of cellular response to mechanical cues, researchers have primarily focused on the changes in the cytoskeletal elements, including those in actin filaments, microtubules, and intermediate filaments. The cytoskeletal network, being the primary load bearing element, acts as a sink for the extracellular forces encountered by tissues. However, the participation of various organelles in cellular mechanoresponse remains mostly unknown. How these forces are eventually dissipated to organelles is not well understood.

changes in mitochondrial form or localization during biochemical stimulations, inflammations, cell division or in highly active cells like neurons, muscles and secretory cells are well characterized. In contrast, the variability in form and localization of mitochondria in response to mechanical cues, especially from the stiffness of the extracellular matrix remain poorly understood.

there are emerging discoveries highlighting the mechanosensitivity of mitochondria to mechanical forces. In the tissue microenvironment, matrix stiffness critically influences these forces. Second, both mitochondrial dysregulation and ECM stiffening are hallmarks of cancer and aging. Finally, there exists a reciprocal relationship between cell mechanics and metabolism

 

[SNT Gatchaman]

Upon matrix stiffening, [mitochondria in human epithelial cells] undergo a transition from a homogeneously distributed, filamentous, and highly networked phenotype to a fragmented and less networked phenotype showing perinuclear clustering.

we found that the effect of matrix stiffness is more distinct on mitochondrial localization than on mitochondrial morphology.

we further show that stiffness-sensitive differential localization of filamin is crucial for determining the subcellular localization of mitochondria.

it will be interesting to understand how this perinuclear clustering of fragmented mitochondria is dynamically achieved on matrix stiffening in vivo. It is possible that during matrix stiffening due to fibrosis, mitochondria undergo fragmentation to increase ATP activity, are transported to the nucleus in a retrograde fashion by microtubules, and are finally retained near the nucleus by perinuclear actin structures formed by filamin and associated proteins.

filamin could be a key molecule connecting both mitochondrial form and localization

 

[Sean]

Very interesting.