AKI mitochondrial damage

Mitochondrial damage or dysfunction contribute critically to the pathogenesis of various diseases including AKI.

We believe the mitochondria is positioned to be a critical player in AKI with its dual role as the primary source of energy for each cell and as a key regulator of cell death.

In AKI mitochondrial damage leads to sublethal and lethal injury of kidney tubules, and the consequent loss of renal function. In various models of AKI, mitochondrial dynamics are disrupted, and membrane integrity is compromised, resulting in the release of apoptogenic factors, mitochondrial permeability transition pores (MPTP), loss of membrane potential, energetic failure, and reactive oxygen species production to induce cell injury and death.

Notably, preservation of mitochondrial dynamics, prevention of mitochondrial membrane permeabilization, and/or promotion of mitochondrial biogenesis can protect kidney tubular cells and tissues in AKI. As such, targeting the mitochondria has been proposed as a therapeutic strategy.

UNI-494 is a patented pro-drug of nicorandil which is currently in development for the treatment of AKI. Nicorandil has been shown in preclinical models to improve mitochondrial function by blocking the opening of MPTP pores in the inner mitochondrial membrane.

Medical animation by Visual Science, 2022.

Role of MPTP in Mitochondrial Destruction

Mitochondrial Permeability Transition Pores (MPTP) form due to:

Work overload / Sustained hyperglycemia / Oxidation injury / Increased CA in cytosol / ATP depletion
Open pores cause influx of water and ions, reversing ATP synthesis initially and subsequently inducing mitochondrial lysis and cellular apoptosis.
Mitochondria K(ATP) channels
SUR 2, KIR 6, K+ ATP Channel. Nicorandil/UNI-494 linker cleaved.

Induction/opening of the mitochondrial permeability transition pores (MPTP)  leads to cessation of ATP synthesis, leading to loss of ion homeostasis, cell disintegration and death. 3-5 Mitochondrial damage and dysfunction are recognized as major pathogenic events in a variety of diseases, including both acute and chronic kidney diseases.1, 2, 6-8

Nicorandil binds to K ATP channel on internal mitochondrial membrane

K+ ATP Channel, Nicorandil/UNI-494 linker 'cleaved'
Four Kir6 units tetramerize to form the channel pore and each Kir6 subunit is associated with one SUR subunit.
Nicorandil binds to ATP-sensitive KATP channels found on the inner membrane of mitochondria
Four Kir6 units combine together along with SUR units to form KATP channel pores.
By binding to KATP channel, Nicorandil blocks the opening up MPTP.

PMID: 19787700_Abstract

References:

  1. Tang C & Dong Z. Mitochondria in Kidney Injury: When the Power Plant Fails. J Am Soc Nephrol 2016, 27: 1869-1872.
  2. Linkermann A et al. Regulated cell death in AKI. J Am Soc Nephrol 2014, 25: 2689-2701.
  3. Norenberg MD & Rama Rao KV. The Mitochondrial Permeability Transition in Neurologic Disease. 2007 50: 983-997
  4. Crompton M, et al. Evidence for the presence of a reversible Ca2+-dependent pore activated by oxidative stress in heart mitochondria. 1987; 245: 915-918
  5. Camara AKS et al. Potential Therapeutic Benefits of Strategies Directed to Mitochondria. Antioxidants & Redox Signaling 2010; 13(3): 280-326.
  6. Szeto HH 2017. Pharmacologic Approaches to Improve Mitochondrial Function in AKI and CKD. J Am Soc Nephrol 2017; 28: 2856-2865
  7. Zhan M. Mitochondrial dynamics: regulatory mechanisms and emerging role in renal pathophysiology. Kidney Int 2013; 83(4): 568-581
  8. Che R et al. Mitochondrial dysfunction in the pathophysiology of renal diseases. Am J Physiol Renal Physiol 2013; 306: 367-378