Mitochondria control vitally important functions in cells, including energy production, cell signalling and regulation of cell death. Considering this, any alteration in mitochondrial metabolism would lead to cellular dysfunction and the development of a disease. A large proportion of disorders associated with mitochondria are induced by mutations or chemical inhibition of the mitochondrial complex I — the entry point to the electron transport chain. Subunits of the enzyme NADH: ubiquinone oxidoreductase, are encoded by both nuclear and mitochondrial DNA and mutations in these genes lead to cardio and muscular pathologies and diseases of the central nervous system. Despite such a clear involvement of complex I deficiency in numerous disorders, the molecular and cellular mechanisms leading to the development of pathology are not very clear. In this review, we summarise how lack of activity of complex I could differentially change mitochondrial and cellular functions and how these changes could lead to a pathology, following discrete routes.

Inorganic polyphosphate (polyP) is a polymer compromised of linearly arranged orthophosphate units that are linked through high-energy phosphoanhydride bonds. The chain length of this polymer varies from five to several thousand orthophosphates. PolyP is distributed in the most of the living organisms and plays multiple functions in mammalian cells, it is important for blood coagulation, cancer, calcium precipitation, immune response and many others. Essential role of polyP is shown for mitochondria, from implication into energy metabolism and mitochondrial calcium handling to activation of permeability transition pore (PTP) and cell death. PolyP is a gliotransmitter which transmits the signal in astrocytes via activation of P2Y1 receptors and stimulation of phospholipase C. PolyP-induced calcium signal in astrocytes can be stimulated by different lengths of this polymer but only long chain polyP induces mitochondrial depolarization by inhibition of respiration and opening of the PTP. It leads to induction of astrocytic cell death which can be prevented by inhibition of PTP with cyclosporine A. Thus, medium- and short-length polyP plays role in signal transduction and mitochondrial metabolism of astrocytes and long chain of this polymer can be toxic for the cells.

Alzheimer's disease (AD) is a neurodegenerative disease characterized by the aggregation of amyloid β-peptide (Aβ) into β-sheet-rich fibrils. Although plaques containing Aβ fibrils have been viewed as the conventional hallmark of AD, recent research implicates small oligomeric species formed during the aggregation of Aβ in the neuronal toxicity and cognitive deficits associated with AD. We have demonstrated that oligomers, but not monomers, of Aβ 40 and Aβ 42 were found to induce calcium signalling in astrocytes but not in neurons. This cell specificity was dependent on the higher cholesterol level in the membrane of astrocytes compared with neurons. The Aβ-induced calcium signal stimulated NADPH oxidase and induced increased reactive oxygen species (ROS) production. These events are detectable at physiologically relevant concentrations of Aβ. Excessive ROS production and Ca 2+ overload induced mitochondrial depolarization through activation of the DNA repairing enzyme poly(ADP-ribose) polymerase-1 (PARP-1) and opening mitochondrial permeability transition pore (mPTP). Aβ significantly reduced the level of GSH in both astrocytes and neurons, an effect which is dependent on external calcium. Thus Aβ induces a [Ca 2+ ] c signal in astrocytes which could regulate the GSH level in co-cultures that in the area of excessive ROS production could be a trigger for neurotoxicity. The pineal hormone melatonin, the glycoprotein clusterin and regulation of the membrane cholesterol can modify Aβ-induced calcium signals, ROS production and mitochondrial depolarization, which eventually lead to neuroprotection.