The entangled ER-mitochondrial axis as a potential therapeutic strategy in neurodegeneration: A tangled duo unchained

Abstract

Endoplasmic reticulum (ER) and mitochondrial function have both been shown to be critical events in neurodegenerative diseases. The ER mediates protein folding, maturation, sorting as well acts as calcium storage. The unfolded protein response (UPR) is a stress response of the ER that is activated by the accumulation of misfolded proteins within the ER lumen. Although the molecular mechanisms underlying ER stress-induced apoptosis are not completely understood, increasing evidence suggests that ER and mitochondria cooperate to signal cell death. Similarly, calcium-mediated mitochondrial function and dynamics not only contribute to ATP generation and calcium buffering but are also a linchpin in mediating cell fate. Mitochondria and ER form structural and functional networks (mitochondria-associated ER membranes [MAMs]) essential to maintaining cellular homeostasis and determining cell fate under various pathophysiological conditions. Regulated Ca2+ transfer from the ER to the mitochondria is important in maintaining control of pro-survival/pro-death pathways. In this review, we summarize the latest therapeutic strategies that target these essential organelles in the context of neurodegenerative diseases.

Metabolic signaling functions of ER–mitochondria contact sites: role in metabolic diseases

“…The molecular mechanism underlying the physiopathology of AD is rather unclear, but AD has interestingly been associated with altered metabolism, altered Ca 2+ homeostasis and mitochondrial dysfunction. Consistent with these alterations, several evidence suggested that MAMs may play a role in neurodegenerative diseases, including AD, as recently highlighted by several reviews (Volgyi et al 2015, Area-Gomez & Schon 2016, Joshi et al 2016, Krols et al 2016, Paillusson et al 2016. Indeed, presenilins are enriched at MAM (Area-Gomez et al 2009).…”

The Unfolded Protein Response: At the Intersection between Endoplasmic Reticulum Function and Mitochondrial Bioenergetics

“…In mouse models of diabetes—where ER stress is chronically active and MAMs are augmented—experimental manipulation of MAMs’ formation restores glucose homeostasis (13). Along these lines, different pathologies of the central nervous system with a strong ER stress component (14) also develop alterations in MAMs either at the morphological or biochemical level (15). Thus, under acute or chronic ER stress, there is an abnormal cross talk between the ER and mitochondria that may drive pathological events impacting metabolic function, redox balance, and cell death control.…”

The Antibiotic Drug Tigecycline: A Focus on its Promising Anticancer Properties

“…Inhibition of mitochondrial respiration by Hedgehog inhibitors, such as cyclopamine tartrate, could strongly interfere with cell proliferation and induce apoptosis in NSCLC (Alam et al, 2016b). In addition, studies have demonstrated that based on the context, the mitochondrial mass can serve as either a pro-survival or pro-death modulator in tumor development and progression (Joshi et al, 2016). These “pleiotropic effects” could be influenced by genetic, environmental and tissue-derived differences between tumors.…”