The endoplasmic reticulum (ER) is an organelle that is responsible for many essential subcellular processes. Interconnected narrow tubules at the periphery and thicker sheet-like regions in the perinuclear region are linked to the nuclear envelope. It is becoming apparent that the complex morphology and dynamics of the ER are linked to its function. Mutations in the proteins involved in regulating ER structure and movement are implicated in many diseases including neurodegenerative diseases such as Alzheimer’s, Parkinson’s, and amyotrophic lateral sclerosis (ALS). The ER is also hijacked by pathogens to promote their replication. Bacteria such as Legionella pneumophila and Chlamydia trachomatis, as well as the Zika virus, bind to ER morphology and dynamics-regulating proteins to exploit the functions of the ER to their advantage. This review covers our understanding of ER morphology, including the functional subdomains and membrane contact sites that the organelle forms. We also focus on ER dynamics and the current efforts to quantify ER motion and discuss the diseases related to ER morphology and dynamics.

/pdf/intertwined-and-finely-balanced-endoplasmic-reticulum-5ebm87r4tr.pdf

Intertwined and Finely Balanced: Endoplasmic Reticulum Morphology, Dynamics, Function, and Diseases.

The panoramic view of amyotrophic lateral sclerosis: A fatal intricate neurological disorder.

Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurological disease affecting both upper and lower motor neurons. In the United States alone, there are 16,000-20,000 established cases of ALS. The early disease diagnosis is challenging due to many overlapping pathophysiologies with other neurological diseases. The etiology of ALS is unknown; however, it is divided into two categories: familial ALS (fALS) which occurs due to gene mutations & contributes to 5-10% of ALS, and sporadic ALS (sALS) which is due to environmental factors & contributes to 90-95% of ALS. There is still no curative treatment for ALS: palliative care and symptomatic treatment are therefore essential components in the management of these patients. In this review, we provide a panoramic view of ALS, which includes epidemiology, risk factors, pathophysiologies, biomarkers, diagnosis, therapeutics (natural, synthetic, gene-based, pharmacological, stem cell, extracellular vesicles, and physical therapy), controversies (in the clinical trials of ALS), the scope of nanomedicine in ALS, and future perspectives. 

The panoramic view of amyotrophic lateral sclerosis: A fatal intricate neurological disorder

The Mitofusin 2 protein (MFN2), encoded by the MFN2 gene, was first described for its role in mediating mitochondrial fusion. However, MFN2 is now recognized to play additional roles in mitochondrial autophagy (mitophagy), mitochondrial motility, lipid transfer, and as a tether to other organelles including the endoplasmic reticulum (ER) and lipid droplets. The tethering role of MFN2 is an important mediator of mitochondrial-ER contact sites (MERCs), which themselves have many important functions that regulate mitochondria, including calcium homeostasis and lipid metabolism. Exemplifying the importance of MFN2, pathogenic variants in MFN2 are established to cause the peripheral neuropathy Charcot-Marie-Tooth Disease Subtype 2A (CMT2A). However, the mechanistic basis for disease is not clear. Moreover, additional pathogenic phenotypes such as lipomatosis, distal myopathy, optic atrophy, and hearing loss, can also sometimes be present in patients with CMT2A. Given these variable patient phenotypes, and the many cellular roles played by MFN2, the mechanistic underpinnings of the cellular impairments by which MFN2 dysfunction leads to disease are likely to be complex. Here, we will review what is known about the various functions of MFN2 that are impaired by pathogenic variants causing CMT2A, with a specific emphasis on the ties between MFN2 variants and MERCs.

/pdf/the-role-of-impaired-mitochondrial-dynamics-in-mfn2-mediated-1vmcqvfo.pdf

The Role of Impaired Mitochondrial Dynamics in MFN2-Mediated Pathology

Amyotrophic Lateral Sclerosis (ALS), neurodegenerative motor neuron disorder is characterized as multisystem disease with important contribution of genetic factors. The etiopahogenesis of ALS is not fully elucidate, but the dominant theory at present relates to RNA processing, as well as protein aggregation and miss-folding, oxidative stress, glutamate excitotoxicity, inflammation and epigenetic dysregulation. Additionally, as mitochondria plays a leading role in cellular homeostasis maintenance, a rising amount of evidence indicates mitochondrial dysfunction as a substantial contributor to disease onset and progression. The aim of this review is to summarize most relevant findings that link genetic factors in ALS pathogenesis with different mechanisms with mitochondrial involvement (respiratory chain, OXPHOS control, calcium buffering, axonal transport, inflammation, mitophagy, etc.). We highlight the importance of a widening perspective for better understanding overlapping pathophysiological pathways in ALS and neurodegeneration in general. Finally, current and potentially novel therapies, especially gene specific therapies, targeting mitochondrial dysfunction are discussed briefly.

Current Concepts on Genetic Aspects of Mitochondrial Dysfunction in Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease for which there is currently no cure. Progress in the characterization of other neurodegenerative mechanisms has shifted the spotlight onto an intracellular structure called mitochondria-endoplasmic reticulum (ER) contacts (MERCs) whose ER portion can be biochemically isolated as mitochondria-associated membranes (MAMs). Within the central nervous system (CNS), these structures control the metabolic output of mitochondria and keep sources of oxidative stress in check via autophagy. The most relevant MERC controllers in the ALS pathogenesis are vesicle-associated membrane protein-associated protein B (VAPB), a mitochondria-ER tether, and the ubiquitin-specific chaperone valosin containing protein (VCP). These two systems cooperate to maintain mitochondrial energy output and prevent oxidative stress. In ALS, mutant VAPB and VCP take a central position in the pathology through MERC dysfunction that ultimately alters or compromises mitochondrial bioenergetics. Intriguingly, both proteins are targets themselves of other ALS mutant proteins, including C9orf72, FUS, or TDP-43. Thus, a new picture emerges, where different triggers cause MERC dysfunction in ALS, subsequently leading to well-known pathological changes including endoplasmic reticulum (ER) stress, inflammation, and motor neuron death.

Amyotrophic Lateral Sclerosis (ALS): Stressed by Dysfunctional Mitochondria-Endoplasmic Reticulum Contacts (MERCs).

Cells must adjust their redox state to an ever-changing environment that could otherwise result in compromised homeostasis. An obvious way to adapt to changing redox conditions depends on cysteine ...

https://journals.sagepub.com/doi/pdf/10.1177/25152564211001213

Post-Translational Modification of Cysteines: A Key Determinant of Endoplasmic Reticulum-Mitochondria Contacts (MERCs):

The endoplasmic reticulum kinase PERK interacts with the oxidoreductase ERO1 to metabolically adapt mitochondria.

S-Palmitoylation of calcineurin β1 connects cellular Ca2+ homeostasis to phosphatidylinositol 4-kinase activity at the plasma membrane.

Mitochondria are key signaling hubs for innate immune responses. In this issue, Wu et al (2022) report that remodeling of the outer mitochondrial membrane by the linear ubiquiting chain assembly complex (LUBAC) facilitates transport of activated NF‐κB to the nucleus in response to TNF signaling.

Junsheng Chen

Papers

Amyotrophic Lateral Sclerosis (ALS): Stressed by Dysfunctional Mitochondria-Endoplasmic Reticulum Contacts (MERCs).

Post-Translational Modification of Cysteines: A Key Determinant of Endoplasmic Reticulum-Mitochondria Contacts (MERCs):

The endoplasmic reticulum kinase PERK interacts with the oxidoreductase ERO1 to metabolically adapt mitochondria.

S-Palmitoylation of calcineurin β1 connects cellular Ca2+ homeostasis to phosphatidylinositol 4-kinase activity at the plasma membrane.

LUBAC and NF‐κB trigger a nuclear response from mitochondria