The contribution of mitochondria-associated ER membranes to cholesterol homeostasis.

Cellular demands for cholesterol are met by a balance between its biosynthesis in the endoplasmic reticulum (ER) and its uptake from lipoproteins. Cholesterol levels in intracellular membranes form a gradient maintained by a complex network of mechanisms including the control of the expression, compartmentalization and allosteric modulation of the enzymes that balance endogenous and exogenous sources of cholesterol. Low-density lipoproteins (LDLs) are internalized and delivered to lysosomal compartments to release their cholesterol content, which is then distributed within cellular membranes.

Two serial filters control P2X7 cation selectivity, Ser342 in the central pore and lateral acidic residues at the cytoplasmic interface.

The human P2X7 receptor (hP2X7R) is a homotrimeric cell surface receptor gated by extracellular ATP with two transmembrane helices per subunit, TM1 and TM2. A ring of three S342 residues, one from each pore-forming TM2 helix, located halfway across the membrane bilayer, functions to close and open the gate in the apo and ATP-bound open states, respectively. The hP2X7R is selective for small inorganic cations, but can also conduct larger organic cations such as Tris.

Aberrant ER-mitochondria communication is a common pathomechanism in mitochondrial disease.

Genetic mutations causing primary mitochondrial disease (i.e those compromising oxidative phosphorylation [OxPhos]) resulting in reduced bioenergetic output display great variability in their clinical features, but the reason for this is unknown. We hypothesized that disruption of the communication between endoplasmic reticulum (ER) and mitochondria at mitochondria-associated ER membranes (MAM) might play a role in this variability.

Towards a Unitary Hypothesis of Alzheimer's Disease Pathogenesis.

The "amyloid cascade" hypothesis of Alzheimer's disease (AD) pathogenesis invokes the accumulation in the brain of plaques (containing the amyloid-β protein precursor [AβPP] cleavage product amyloid-β [Aβ]) and tangles (containing hyperphosphorylated tau) as drivers of pathogenesis. However, the poor track record of clinical trials based on this hypothesis suggests that the accumulation of these peptides is not the only cause of AD. Here, an alternative hypothesis is proposed in which the AβPP cleavage product C99, not Aβ, is the main culprit, via its role as a regulator of cholesterol metabolism.

Mitochondrial disease: Replace or edit?

Questions over mitochondrial replacement suggest a role for mitochondrial DNA editing.