Presenilins and mitochondria-an intriguing link: mini-review

Abstract

This review uncovers the intricate relationship between presenilins, calcium, and mitochondria in the context of Alzheimer's disease (AD), with a particular focus on the involvement of presenilin mutations in mitochondrial dysfunction. So far, it is unclear whether the impairment of mitochondrial function arises primarily from damage inflicted by β-amyloid upon mitochondria or from the disruption of calcium homeostasis due to presenilins dysfunctions. The roles of presenilins in mitophagy, autophagy, mitochondrial dynamics, and many other functions, non-γ-secretase related, also require close attention in future research. Resolution of contradictions in understanding of presenilins cellular functions are needed for new effective therapeutic strategies for AD.

Keywords: Alzheimer’s disease; mitochondria associated membranes; neurodegeneration; presenilins; spine apparatus.

Figure 1

Multiple effects of presenilin (PS) dysfunction. Presenilin mutations result in an overload of calcium (Ca²⁺) within the spine apparatus (SA) due to decreased leakage via (1) pore of PS itself and (2) reduced influence of PS on RYR channels. This excessive calcium accumulation leads to impaired calcium conduction into mitochondria and decreased ATP production and therefore energy support of postsynaptic processes. (3) Presenilin mutations disrupt retrograde transport and cause dendrite obstruction. (4) Presenilin mutations lead to a reduction in connections between kinesin and membrane-bound organelles, such as mitochondria. (5) Mutations in presenilin result in extensive mitochondrial fission and impaired mitochondria-ER contact at mitochondria-associated membranes (MAMs). (6) Presenilin influences mitophagy by participating in the activation of transcription factors of PINK1 genes, which are essential for recruiting ubiquitin ligase PARKIN to the mitochondrial membrane and establishing a connection with the phagophore membrane. (7) Dysregulation of calcium homeostasis hampers autophagy by impairing lysosomal fusion. RYR, ryanodine receptor; SERCA, sarco/endoplasmic reticulum Ca²⁺-ATPase; and VDAC, voltage-dependent anion channels. In the figure, a red cross denotes the inhibition of a process.