Remodelling of the plasma membrane cytoarchitecture is crucial for the regulation of epithelial cell adhesion and permeability. In Madin-Darby canine kidney cells, the protein AHNAK relocates from the cytosol to the cytosolic surface of the plasma membrane during the formation of cell–cell contacts and the development of epithelial polarity. This targeting is reversible and regulated by Ca2+-dependent cell–cell adhesion. At the plasma membrane, AHNAK associates as a multimeric complex with actin and the annexin 2/S100A10 complex. The S100A10 subunit serves to mediate the interaction between annexin 2 and the COOH-terminal regulatory domain of AHNAK. Down-regulation of both annexin 2 and S100A10 using an annexin 2–specific small interfering RNA inhibits the association of AHNAK with plasma membrane. In Madin-Darby canine kidney cells, down-regulation of AHNAK using AHNAK-specific small interfering RNA prevents cortical actin cytoskeleton reorganization required to support cell height. We propose that the interaction of AHNAK with the annexin 2/S100A10 regulates cortical actin cytoskeleton organization and cell membrane cytoarchitecture.

In response to cellular and environmental stresses, mitochondria undergo morphology transitions regulated by dynamic processes of membrane fusion and fission. These events of mitochondrial dynamics are central regulators of cellular activity, but the mechanisms linking mitochondrial shape to cell function remain unclear. One possibility evaluated in this review is that mitochondrial morphological transitions (from elongated to fragmented, and vice-versa) directly modify canonical aspects of the organelle's function, including susceptibility to mitochondrial permeability transition, respiratory properties of the electron transport chain, and reactive oxygen species production. Because outputs derived from mitochondrial metabolism are linked to defined cellular signaling pathways, fusion/fission morphology transitions could regulate mitochondrial function and retrograde signaling. This is hypothesized to provide a dynamic interface between the cell, its genome, and the fluctuating metabolic environment. mitochondrial dynamics; morphology; fusion and fission; bioenergetics; retrograde signaling MITOCHONDRIA are crucial organelles involved in cellular energy production and in the regulation of numerous aspects of cellular activity, including, but not limited to, apoptosis, Ca 2ϩ signaling, and redox homeostasis (41). Over the last decade, mitochondria have moved to the forefront of cell biology research for their ability to undergo regulated events of membrane fusion and fission, which remodel the architecture of the mitochondrial network within the cytoplasm (43,36,146). Processes of mitochondrial fusion and fission are collectively termed mitochondrial dynamics. Importantly, abnormal mitochondrial dynamics cause bioenergetic defects (26), induce embryonic lethality in transgenic animal models (27), and underly a heterogenous group of human diseases (164), attesting to the pivotal role of these processes in physiopathology (25,50,91). In addition, experimental work has shown that mitochondrial dynamics are involved in regulating cellular activity and that mitochondria participate in important cellular signaling pathways (136,158).Mitochondrial retrograde signaling is defined as the transfer of information from mitochondria to the cytoplasm and nucleus. Retrograde signaling pathways have been established to occur in response to metabolic perturbations, with the aim to trigger adaptive cellular responses orchestrated by coordinated changes in gene expression (reviewed in Refs. 21 and 93). Among the retrograde signals produced by mitochondria that are known to regulate different aspects of cellular activity, the most studied include reactive oxygen species (ROS), pro-apoptotic molecules, ATP/ADP/AMP, metabolic intermediates (NAD ϩ /NADH), and Ca 2ϩ (20,39,58). From recent discoveries revealing that mitochondrial dynamics regulate cellular activity in response to various stressors, it is hypothesized that changes in mitochondrial morphology regulate, either directly or indirectly, various aspects of mitochondrial funct...

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS [MIM 270550]) is an early-onset neurodegenerative disorder caused by mutations in the SACS gene. Over 170 SACS mutations have been reported worldwide and are thought to cause loss of function of sacsin, a poorly characterized and massive 520 kDa protein. To establish an animal model and to examine the pathophysiological basis of ARSACS, we generated Sacs knockout (Sacs(-/-)) mice. Null animals displayed an abnormal gait with progressive motor, cerebellar and peripheral nerve dysfunctions highly reminiscent of ARSACS. These clinical features were accompanied by an early onset, progressive loss of cerebellar Purkinje cells followed by spinal motor neuron loss and peripheral neuropathy. Importantly, loss of sacsin function resulted in abnormal accumulation of non-phosphorylated neurofilament (NF) bundles in the somatodendritic regions of vulnerable neuronal populations, a phenotype also observed in an ARSACS brain. Moreover, motor neurons cultured from Sacs(-/-) embryos exhibited a similar NF rearrangement with significant reduction in mitochondrial motility and elongated mitochondria. The data points to alterations in the NF cytoskeleton and defects in mitochondrial dynamics as the underlying pathophysiological basis of ARSACS.