Mitochondria and endoplasmic reticulum crosstalk in amyotrophic lateral sclerosis

Abstract

Physical and functional interactions between mitochondria and the endoplasmic reticulum (ER) are crucial for cell life. These two organelles are intimately connected and collaborate to essential processes, such as calcium homeostasis and phospholipid biosynthesis. The connections between mitochondria and endoplasmic reticulum occur through structures named mitochondria associated membranes (MAMs), which contain lipid rafts and a large number of proteins, many of which serve multiple functions at different cellular sites. Growing evidence strongly suggest that alterations of ER-mitochondria interactions are involved in neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS), a devastating and rapidly fatal motor neuron disease. Mutations in proteins that participate in ER-mitochondria interactions and MAM functions are increasingly being associated with genetic forms of ALS and other neurodegenerative diseases. This evidence strongly suggests that, rather than considering the two organelles separately, a better understanding of the disease process can derive from studying the alterations in the their crosstalk. In this review we discuss normal and pathological ER-mitochondria interactions and the evidence that link them to ALS.

Endoplasmic reticulum–mitochondria crosstalk: from junction to function across neurological disorders

“…Amyotrophic lateral sclerosis (ALS) is a devastating motor neuron disorder, associated with progressive muscle weakness, paralysis, and death within a few years of onset . Sporadic ALS cases are more than familial type of ALS (fALS).…”

“…Fused in sarcoma (FUS), transactive response DNA‐binding protein 43 (TDP‐43), ubiquitin‐2, VAPB, and protein disulfide isomerase (PDI) are few of the proteins encoded by these genes . All these aberrations are considered as major pathological events in ALS, as these mutated proteins have been observed in glia and neurons of ALS patients . Overexpression of these proteins alters the ER–mitochondria contact proteins structurally and functionally .…”

“…Alterations in ER–mitochondria communications could be a primary event in ALS, as they are affected globally in all cell types. Yet, there is no treatment for ALS except riluzole, a benzothiazole derivative with neuroprotective and potential antidepressant and anxiolytic activities, which increases the survival period by only 2–3 months …”

Discrete mitochondrial aberrations in the spinal cord of sporadic ALS patients

“…As mentioned above, likely sALS oligodendrocytes show little if any mitochondrial dysfunction and mitochondria present in motor neurons and/or neuronal synapses in gray matter are a major contributor to the spinal cord mitochondrial dysfunction in ALS (S Sasaki & Iwata, ). However, it is also possible that mitochondria in the neuronal cell bodies, which are in close proximity to the endoplasmic reticulum (ER), are exposed to higher levels of ER‐released Ca 2+ that stimulates mitochondrial citric acid cycle metabolism and ETC activity to increase ROS production leading to oxidative damage (Manfredi & Kawamata, ; Pinton, Giorgi, Siviero, Zecchini, & Rizzuto, ). Increased Ca 2+ levels may also stimulate nitric oxide synthase leading to nitric oxide‐mediated inhibition of complex IV (Beal, ).…”

Capturing intracellular Ca 2+ dynamics in computational models of neurodegenerative diseases

“…Mitochondrial dysfunction and alteration in ER-mitochondria crosstalk are thought to be primarily involved in Ca 2+ dysregulation in ALS affected motor neurons [15] (also see review [16]). Excessive mitochondrial Ca 2+ accumulation can cause the opening of the mitochondrial permeability transition pore, which has been associated with activation of cell death pathways [17].…”