Mitochondria in Acute Kidney Injury

doi:10.1016/j.semnephrol.2016.01.005

Seminars in Nephrology

Volume 36, Issue 1, January 2016, Pages 8-16

https://doi.org/10.1016/j.semnephrol.2016.01.005 Get rights and content

Summary

Acute kidney injury (AKI) continues to be a significant contributor to morbidity, mortality, and health care expenditure. In the United States alone, it is estimated that more than $10 billion is spent on AKI every year. Currently, there are no available therapies to treat established AKI. The mitochondrion 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. This review aims to cover the current state of research on the role of mitochondria in AKI, while also proposing potential therapeutic targets and future therapies.

Section snippets

Mitochondrial structure

The mitochondrion is uniquely structured to function as the powerhouse for the cell (Fig. 2). Each mitochondrion is composed of an inner and an outer membrane, which are separated by the intermembrane space. The outer membrane contains a channel protein, called porin, which allows the passage of molecules less than approximately 5,000 daltons to pass freely into the intermembrane space. In contrast, the inner membrane is highly impermeable to ions and small molecules and contains many folds,

Renal Manifestations Of Genetic Disorders Of The Mitochondrion

Mutations in mtDNA often disrupt oxidative phosphorylation and primarily affect organs with high rates of energy consumption, including skeletal muscle, the central nervous system, the heart, and the kidneys. Signs that a clinical syndrome may be of mitochondrial origin include early age of onset, multiorgan system involvement, increased lactic acid level, and a pattern of maternal inheritance. The proximal tubule is often affected given its high density of mitochondria; as a result, Fanconi

Evidence For Mitochondrial Involvement In Aki

In addition to being the primary source of energy for maintaining cell function, mitochondria are also a source of many substances that can lead to cell death. These seemingly paradoxic roles of the mitochondrion are tightly regulated in healthy cells. In response to cell injury or hypoxia, further damage can be caused by the release of ROS or activation of the caspase system, leading to apoptosis.

It is notable that after an insult, mitochondrial injury appears to precede the clinical

Approaches For Mitochondrial Targeting

As alluded to earlier, mitochondria are poised at the intersection of life and death for cells with high metabolic needs. Intense ATP production is necessary for cells of the proximal tubule and medullary thick ascending limb to reabsorb solutes through active transport. Moreover, ATP powers the electrogenic cell-surface ATPase that counteracts the constant threat of cell swelling from the passive entry of sodium ions and water. On the other hand, in response to various noxious stimuli,

Implications For Immune Pathways During Repair

Mitochondrial injury may be central to AKI pathogenesis. Moreover, mitochondrial biogenesis and mitophagy may be essential elements of recovery in tubular cells that have suffered sublethal injury. Relatively few studies have directly examined whether mitochondrial processes directly influence long-term outcomes after AKI, such as maladaptive repair leading to fibrosis.

Populations of both resident macrophages and blood-derived monocytes homing to injured renal tissue expand in number after

Future Horizons

Mitochondria may be a promising target for both the diagnosis and treatment of AKI. Given that mitochondrial injury appears to precede the clinical manifestations of AKI, one could envision noninvasive methods that assess kidney mitochondrial function as a marker of injury. Such information could be useful in several clinical scenarios, including the monitoring of patients with delayed graft function after renal transplant, determining the appropriate time to stop renal replacement therapy in

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Although the intrinsic toxicity of antibiotics against proximal tubule cells is not entirely known, mitochondrial injury is commonly cited as a potential cause because mitochondria are highly abundant in the kidney and work as the primary energy source for kidney cell function [8,9]. Changes to kidney mitochondrial integrity are often seen prior to the clinical manifestation of AKI [9]. A proposed mechanism involves the uptake of antibiotics into lysosomes, which subsequently leak into the cell cytoplasm and cause injury to multiple organelles, including the mitochondria [10].
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IR was associated with reduced renal function and slightly elevated blood pressure, in combination with renal injuries, inflammation, endothelial dysfunction, increased Ang II levels and Ang II-mediated vasoreactivity, which were all ameliorated by nitrate. Moreover, treatment with nitrate (in vivo) and nitrite (in vitro) restored NO bioactivity and reduced mitochondrial oxidative stress and injuries.
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^☆: Financial support: Studies on mitochondria and metabolism in the Parikh Laboratory are supported in part by the National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK095072).

^☆☆: Conflict of interest statement: none.

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Mitochondria in Acute Kidney Injury☆,☆☆

Summary

Section snippets

Mitochondrial structure

Renal Manifestations Of Genetic Disorders Of The Mitochondrion

Evidence For Mitochondrial Involvement In Aki

Approaches For Mitochondrial Targeting

Implications For Immune Pathways During Repair

Future Horizons

Hum Pathol

Kidney Int

Biochim Biophys Acta

Exp Cell Res

Am J Human Genet

Arch Biochem Biophys

Curr Top Dev Biol

Kidney Int

J Pediatr

Biochim Biophys Acta

Hum Pathol

Kidney Int

Kidney Int

Kidney Int

Free Radic Biol Med

Biochim Biophys Acta

Curr Opin Cell Biol

Semin Nephrol

Cell

Cell

J Biol Chem

Kidney Int

Transplant Rev (Orlando)

Mitochondrion

Mitochondria: a historical review

J Cell Biol

Uber sauerstoffatmende koernchen aus leberzellen und uber sauerstoffatmung in berekfeld-filtralen wassriger leverextrakte

Arch Gesamte Physiol

On cytochrome, a respiratory pigment, common to animals, yeast, and higher plants

Proc R Soc Lond B Biol Sci

Metabolism of ketonic acids in animal tissues

Biochem J

The fine structure of mitochondria

Anat Rec

Relationships between urea extraction, renal blood flow, renal oxygen consumption, and diuresis. The mechanism of urea excretion

Am J Physiol

The fuel of respiration of rat kidney cortex

Biochem J

Human renal ultrastructure. I. Proximal tubule of healthy individuals

Lab Invest

Polyene toxicity in renal medulla: injury mediated by transport activity

Science

Functions and dysfunctions of mitochondrial dynamics

Nat Rev Mol Cell Biol

Mitochondrial dynamics—mitochondrial fission and fusion in human diseases

N Engl J Med

Oxidative phosphorylation and photophosphorylation

Ann Rev Biochem

Coupling of phosphorylation to electron and hydrogen transfer by a chemi-osmotic type of mechanism

Nature

Mitochondrial evolution

Science

Sequence and organization of the human mitochondrial genome

Nature

Prevalent coordination of mitochondrial DNA transcription and initiation of replication with the cell cycle

Nucleic Acids Res

Transcriptional regulatory circuits controlling mitochondrial biogenesis and function

Genes Dev

Adaptations of skeletal muscle to exercise: rapid increase in the transcriptional coactivator PGC-1

FASEB J

Elimination of paternal mitochondrial DNA in intraspecific crosses during early mouse embryogenesis

Proc Natl Acad Sci U S A

Maternal inheritance of mouse mtDNA in interspecific hybrids: segregation of the leaked paternal mtDNA followed by the prevention of subsequent paternal leakage

Genetics