Dysfunction of Mitochondria in Alzheimer’s Disease: ANT and VDAC Interact with Toxic Proteins and Aid to Determine the Fate of Brain Cells
Abstract
:1. Introduction
2. Mitochondria—What You Need to Know to Understand the Rest!
3. Proteinopathy and Mitochondrial Dysfunction in AD: A Marriage
4. ANT and VDAC Both Interact with AD Toxic Proteins
- (i)
- ANT hosts two (opposite) functions, both involved in the control and regulation of cell fate [65,66]: one vital function, the other lethal. The vital role of ANT is the enzymatic one, which is the historical and the main function to catalyze the carrier-mediated exchange between the cytosolic ADP with the ATP formed in the matrix, by facilitating the export of the newly synthesized ATP into the cell and, at the same time, by providing ADP as a substrate available for its mitochondrial phosphorylation to ATP by ATP synthase. This function has been extensively characterized in mitochondria isolated from various tissues with radiolabelled nucleotides and in native ANT-containing proteoliposomes [67,68,69], but not only [70], as we will see! The lethal function of ANT, which occurs in conditions of cellular ‘sickness’, is associated with its involvement as a component of the mitochondrial permeability transition pore (mPTP), a structure that forms in the inner mitochondrial membrane and is thought to underlie regulated cell death [71,72].
- (ii)
- VDAC1 is the most abundant protein in the MOM since its discovery in 1976 [73]. Although its localization remains predominantly mitochondrial (mVDAC), VDAC has been found on the plasma membrane (plVDAC) of cells. Besides, although plVDAC has been extensively studied, its exact biological function is not yet known, and we will not address it here. Therefore, in this review, we will refer to mitochondrial VDAC as VDAC. Previously, VDAC was considered responsible for the near-free permeability of the MOM [73] or a large mesh sieve [74], but nowadays, it unexpectedly stands as a gatekeeper for the entry and exit of mitochondrial metabolites, thus controlling the cross-talk between the mitochondria and the rest of the cellular compartments [75,76]. Not surprisingly, therefore, VDAC has been implicated in a wide range of pathologies associated with mitochondria [77,78,79]. It is believed that the uniqueness of this channel derives from its key position at the interface between the mitochondrion and the cytosol [77,78,79,80], thus becoming an important hub protein that interacts with over 200 proteins [81,82,83] that regulate the permeability of the MOM. A plethora of cytosolic proteins, glycolytic, such as hexokinase, and other enzymes [78], as well as their neighbors in the MOM, such as the cholesterol transporter, [78] as well as proteins of the family Bcl-2 [78], interact with VDAC. An acute observation by Reina and De Pinto [84] pointed out to the world that the high diversity of natural and synthetic ligands with which VDAC interacts is a symptom of lack of specificity for VDAC, so that this protein is not used to being considered a reliable drug target.
4.1. ANT
- (i)
- The rate of appearance of ATP was reduced when Aβ1–42 or NH2-26–44-tau was added before ADP.
- (ii)
- The extent of inhibition was less than that found when the NH2-tau fragment was added alone if the incubation of homogenate with Aβ1–42 preceded the addition of NH2-26–44-tau, suggesting that the binding of Aβ1–42 to ANT1 resulted in a conformational change of the transporter protein, making it less accessible to the NH-tau fragment. This only happens if Aβ 1–42 is added before the tau fragment, but not vice versa, suggesting that Aβ 1–42 acts as a negative modulator of mitochondrial NH2-tau fragment toxicity and not vice versa;
- (iii)
- The extent of inhibition increased strongly when the two peptides, NH2-26–44-tau and fibrillar Aβ1–42, were added together, confirming that the two peptides together cooperate by potentiating ANT-1 dysfunction and further aggravating the production of ATP.
4.2. VDAC
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Atlante, A.; Valenti, D.; Latina, V.; Amadoro, G. Dysfunction of Mitochondria in Alzheimer’s Disease: ANT and VDAC Interact with Toxic Proteins and Aid to Determine the Fate of Brain Cells. Int. J. Mol. Sci. 2022, 23, 7722. https://doi.org/10.3390/ijms23147722
Atlante A, Valenti D, Latina V, Amadoro G. Dysfunction of Mitochondria in Alzheimer’s Disease: ANT and VDAC Interact with Toxic Proteins and Aid to Determine the Fate of Brain Cells. International Journal of Molecular Sciences. 2022; 23(14):7722. https://doi.org/10.3390/ijms23147722
Chicago/Turabian StyleAtlante, Anna, Daniela Valenti, Valentina Latina, and Giuseppina Amadoro. 2022. "Dysfunction of Mitochondria in Alzheimer’s Disease: ANT and VDAC Interact with Toxic Proteins and Aid to Determine the Fate of Brain Cells" International Journal of Molecular Sciences 23, no. 14: 7722. https://doi.org/10.3390/ijms23147722