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the role of mitochondria in systemic disease has been under - appreciated , and in this issue of critical care , ct et al .  
however , recent evidence has demonstrated impaired oxidative phosphorylation and defective mitochondrial homeostasis in a number of disorders .
although the concept of mitochondrial dysfunction and bioenergetic failure during sepsis and shock is not new , recent experimental approaches have yielded novel and interesting findings [ 4 - 6 ] . these have led us and others to propose intriguing hypotheses regarding the pathogenesis of acquired mitochondrial dysfunction in a variety of disease states . in this issue , ct et al .
their data demonstrate a 30% reduction in the ratio of mtdna to nuclear dna ( ndna ) in circulating cells of 28 critically ill patients when compared to healthy controls .
more importantly , this ratio increased by almost 30% at four days in survivors while non - survivors experienced a further reduction in the mtdna / ndna ratio .
one might conclude that loss or failed synthesis of mtdna is a unifying cause of sepsis - induced mitochondrial dysfunction and that clinicians could use mtdna copy number to predict mortality during critical illness .
these encode for 13 essential subunits of electron transport chain enzymes , two ribosomal rnas and 22 transfer rnas .
the structural subunits of the electron transport complexes and other mitochondrial proteins arise from nuclear genes .
mtdna is particularly prone to deletions , rearrangements and mutations caused by oxidative stress because it is unbound by histones and because these organelles lack the extensive repair systems seen in the nucleus .
therefore , reactive oxygen species produced during oxidative phosphorylation in a variety of disease states can damage mtdna and mitochondrial proteins
heteroplasmy describes the coexistence of both mutant mtdna and wild - type , non - mutant mtdna within the same cell . if the mitochondrial genome drift results in a significant amount of mutant mtdna , cells exhibit reduced energy capacity and organs become dysfunctional .
the threshold for these processes is lower in highly oxidative tissue such as brain , heart , skeletal muscle , retina , kidney and endocrine organs .
this threshold effect explains tissue - related variability in the clinical presentation of both inherited and acquired mitochondrial diseases .
impaired mitochondrial biogenesis represents an additional manner in which mitochondria may contribute to acquired disorders .
it requires precise coordination between both mitochondrial and nuclear - encoded gene products as well as maintenance and replication of mtdna .
recent investigation demonstrates that experimental murine sepsis caused mitochondrial oxidative stress , a loss of mtdna copy number and depressed basal metabolism in the septic liver . in the recovery phase , mitochondrial biogenesis restored mtdna copy number and oxidative metabolism .
our understanding of bioenergetic failure in sepsis and shock has been largely limited by interpretation of early investigations .
however , more recent data make it clear that cells can adapt and maintain viability by down - regulating oxygen consumption , energy requirements and atp demand . in the heart
this response is called myocardial hibernation and results in cardiomyocyte hypocontractility with preserved cellular atp .
hibernating cells maintain atp levels in the setting of defective oxidative phosphorylation by ceasing nonessential cellular functions to limit atp utilization . at the organ level
, this down - regulated metabolic state may manifest as " organ dysfunction " or " organ failure " . during hypoxia , ischemia and in early or non - fatal sepsis , such a response appears to be adaptive and often reversible as cells at risk maintain viability and recover after reoxygenation and reperfusion .
our data , however , indicate that during lethal sepsis a similar hibernation response , while initially adaptive , may become problematic as cells remain persistently down - regulated , enzyme complex content and activity decrease and organ failure becomes irreversible .
this may result from an acquired defect in gene expression and/or functional activity of any of the electron transport enzymes .
our data suggest that persistently impaired mitochondrial gene expression may represent the irreversible defect that leads to organ failure and death .
the hypothesis that therapeutically enhancing mitochondrial biogenesis could improve survival is fascinating , especially if defects in mitochondrial replication and mtdna synthesis also occur in cells of solid organs .
based on recent reports , it is conceivable that stem cells or fibroblasts may be able to restore defective mitochondria in neighboring cells with wild - type mtdna .
thus , future investigation should focus on increasing and restoring wild - type mtdna to restore cellular oxidative capacity and organ function in sepsis and shock .
what is most exciting is that we are still gaining insight into this billion year old , complex organelle .
however , it remains unclear if mitochondrial impairment causes organ dysfunction , is protective against impending organ injury or is an epiphenomenon .
these questions demand a more exhaustive investigation of the fascinating processes of mitochondrial biogenesis and homeostasis during both health and disease .
the authors ' work is supported by nih / nigms 1k08gm074117 ( rjl ) , maria fareri children 's hospital foundation grant ( rjl ) , nih / nigms 5r01gm059930 ( csd ) .
recent studies indicate that mitochondrial dysfunction plays a role in the pathogenesis of a number of disease states . 
 the importance of these organelles in shock and multiple organ dysfunction is of particular interest to those caring for the critically ill . 
 mitochondria have their own unique dna ( mtdna ) that encodes 13 essential subunits of electron transport chain enzymes , two ribosomal rnas and 22 transfer rnas . 
 importantly , mtdna is especially susceptible to deletions , rearrangements and mutations because it is not bound by histones and lacks the extensive repair machinery present in the nucleus . 
 the study by ct et al . in this issue of critical care examines changes in mtdna in critically ill patients . 
 the results support further investigation into the role of mtdna in the critically ill .