Recent studies undoubtedly show the importance of inter organellar connections to maintain cellular homeostasis. In normal physiological conditions or in the presence of cellular and environmental stress, each organelle responds alone or in coordination to maintain cellular function. The Endoplasmic reticulum (ER) and mitochondria are two important organelles with very specialized structural and functional properties. These two organelles are physically connected through very specialized proteins in the region called the mitochondria-associated ER membrane (MAM). The molecular foundation of this relationship is complex and involves not only ion homeostasis through the shuttling of calcium but also many structural and apoptotic proteins. IRE1alpha and PERK are known for their canonical function as an ER stress sensor controlling unfolded protein response during ER stress. The presence of these transmembrane proteins at the MAM indicates its potential involvement in other biological functions beyond ER stress signaling. Many recent studies have now focused on the non-canonical function of these sensors. In this review, we will focus on ER mitochondrial interdependence with special emphasis on the non-canonical role of ER stress sensors beyond ER stress.

Accumulation of misfolded proteins is a common phenomenon of several neurodegenerative diseases. The misfolding of proteins due to abnormal polyglutamine (PolyQ) expansions are linked to the development of PolyQ diseases including Huntington’s disease (HD). Though the genetic basis of PolyQ repeats in HD remains prominent, the primary molecular basis mediated by PolyQ toxicity remains elusive. Accumulation of misfolded proteins in the ER or disruption of ER homeostasis causes ER stress and activates an evolutionarily conserved pathway called Unfolded protein response (UPR). Protein homeostasis disruption at organelle level involving UPR or ER stress response pathways are found to be linked to HD. Due to dynamic intricate connections between ER and mitochondria, proteins at ER-mitochondria contact sites (mitochondria associated ER membranes or MAMs) play a significant role in HD development. The current review aims at highlighting the most updated information about different UPR pathways and their involvement in HD disease progression. Moreover, the role of MAMs in HD progression has also been discussed. In the end, the review has focused on the therapeutic interventions responsible for ameliorating diseased states via modulating either ER stress response proteins or modulating the expression of ER-mitochondrial contact proteins.

Identification and characterization of a novel mitochondrial fusion agonist beneficial against Huntington's disease (HD) pathology.

Peroxisomal biogenesis factor 11 beta (Pex11β) is a key regulator of peroxisome proliferation, functioning in coordination with mitochondrial fission proteins. Recent human proteome co-regulation mapping has revealed a distinctive co-expression pattern between Pex11β and components of the mitochondrial respiratory chain complex at the peroxisome–mitochondria interface. In neurodegenerative disorders, such as Huntington’s disease (HD) and Alzheimer’s disease (AD), mitochondrial dysfunction is primarily associated with impairments in the respiratory chain complexes, particularly Complex II. However, the role of Pex11β in maintaining mitochondrial homeostasis in these two disease conditions remains largely unexplored. In this study, using both in vitro and in vivo models, we identify Pex11β as a critical modulator of mitochondrial dynamics, influencing the balance between fission and fusion. Through targeted knockdown and overexpression experiments, we demonstrate a direct link between Pex11β level and mitochondrial dysfunction, mediated by transcriptional dysregulation of nuclear-encoded Complex II and mitochondrial fusion genes. Restoration of Pex11β expression, along with Complex II and fusion gene level in striatal brain via a peroxisome proliferator & chemical chaperone, significantly alleviates motor and cognitive deficits in 3-NP-induced HD mouse model indicating better mitochondrial health in striatal brain. Furthermore, in silico analysis and ChIP-qPCR reveal Yin Yang 1 (YY1) is a critical transcription factor governing the co-expression of Pex11β and Complex II genes. This establishes a novel transcriptional axis that orchestrates inter-organellar communication. Collectively, our findings position Pex11β as a pivotal mediator of mitochondrial fission-fusion dynamics, linking mitochondrial morphology and oxidative phosphorylation (OXPHOS) to behavioural outcomes, and offering mechanistic insights relevant to amyloid-associated neurodegenerative diseases.

Emerging evidence links vitamin D (VD) deficiency to cognitive and motor dysfunction in Huntington’s disease (HD), yet the underlying mechanism remains unclear. Here, we combine in vitro genetic and 3-nitropropionic acid (3-NP)-induced in vivo models of HD to define the mechanistic basis of VD-mediated neuroprotection. We demonstrate that VD supplementation restores cognitive and motor deficits while improving mitochondrial function and cellular survival. Mechanistically, VD enhances mitochondrial fusion and rescues complex II expression, a key defect in HD pathology. We identify the mitochondrial enzyme CYP27A1 as a critical mediator of this effect, as its expression is reduced in HD models but restored upon VD treatment. Overexpression of CYP27A1 recapitulates the protective effects of VD, confirming its central role in maintaining mitochondrial integrity. Furthermore, VD promotes vitamin D receptor (VDR)-dependent transcriptional activation of CYP27A1 and additional nuclear- and mitochondrial-encoded genes, establishing a regulatory feedback loop that supports mitochondrial biogenesis and function. VD supplementation also improves proteostasis via attenuating endoplasmic reticulum stress. Together, our findings uncover a previously unrecognized VD–CYP27A1 axis that links mitochondrial dysfunction to HD pathology and highlight CYP27A1 as a potential therapeutic target.