Cytochrome c as a Potentially Clinical Useful Marker of Mitochondrial and Cellular Damage

Abstract

Mitochondria are evolutionary endosymbionts derived from bacteria. Thus, they bear molecules, such as mitochondrial DNA (mtDNA) that contains CpG DNA repeats and N-formyl peptides (FPs), found in bacteria. Upon cell necrosis or apoptosis, these molecules are released into the interstitial space and the circulation and recognized by the immune cells through the same receptors that recognize pathogen-associated molecular patterns, leading to inflammation. Other mitochondrial molecules are not of bacterial origin, but they may serve as danger-associated molecular patterns (DAMPs) when due to cell injury are translocated into inappropriate compartments. There they are recognized by pattern recognition receptors of the immune cells. Cytochrome c is such a molecule. In this review, experimental and clinical data are presented that confirms cytochrome c release into the extracellular space in pathological conditions characterized by cell death. This indicates that serum cytochrome c, which can be easily measured, may be a clinically useful marker for diagnosing and assessing the severity of such pathological entities. Reasonably, detection of high cytochrome c level into the circulation means release of various other molecules that serves as DAMPs when found extracellularly, the mtDNA and FPs included. Finally, because the release of this universally found compound into the extracellular space makes cytochrome c an ideal molecule to play the role of a DAMP per se, the available experimental and clinical data that support such a role are provided.

Silymarin Protects Mouse Liver and Kidney from Thioacetamide Induced Toxicity by Scavenging Reactive Oxygen Species and Activating PI3K-Akt Pathway

“…After the release into the cytosol, cytochrome c forms apoptosomes that activates caspase 9 and other downstream caspases (Eleftheriadis et al, 2016). In the present study, apoptosis was determined by the estimation of caspase-3 activation and PARP cleavage.…”

Mitochondrial dysfunction and damage associated molecular patterns (DAMPs) in chronic inflammatory diseases

“…Upon apoptotic stimuli, the release of cytochrome c into the cytoplasm has been identified to be a critical event to trigger non-inflammatory process of cellular death. In contrast, when translocated into the extracellular space, cytochrome c may function as a mitochondrial DAMP to trigger inflammation and its level could be used as a marker of mitochondrial damage (Eleftheriadis et al, 2016). For example, serum levels of cytochrome c were found increased in patients with myocardial infarction, hepatic inflammation, multiple types of cancers and systemic inflammatory response syndrome.…”

“…For example, serum levels of cytochrome c were found increased in patients with myocardial infarction, hepatic inflammation, multiple types of cancers and systemic inflammatory response syndrome. The measurement of cytochrome c has been suggested to be a clinically useful marker for diagnosing and assessing the severity of these pathologic entities (reviewed in reference; (Eleftheriadis et al, 2016)).…”

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“…Pro and anti-apoptotic members of the bcl-2 family regulate mitochondrial participation in cell death 50 . Earlier models have proposed that the release of cytochrome c from damaged mitochondria triggers the activation of cascade of caspases 51 .…”