VACTERL association is a clinically and causally heterogenous disorder, and the overall mechanism of disease remains incompletely understood. The involvement of many apparently unrelated organ systems, as well as the lack of a definite Mendelian inheritance mode in the majority of instances, suggests the presence of new, currently unidentified mutations in some individuals, as well as the possibility of a more complex multifactorial disorder in other individuals, with genetic, epigenetic, environmental, and more purely stochastic factors combinatorially involved in disease pathogenesis.
To date, no common causal link between mitochondrial dysfunction and the development of VACTERL association has been demonstrated. Mitochondrial dysfunction might not be the sole cause for the vast majority of individuals with VACTERL association, but could play a role through increasing tissue susceptibility to aberrant development. Additionally, the recognition of the involvement of mitochondrial dysfunction in the development of congenital anomalies through impaired energy production, reactive oxygen species generation and aberrant apoptosis in well-established disorders opens the door for further discussion, investigation and research in the fast developing field of complex disorders, including explanations of variable disease expression in some Mendelian conditions. For example, even in well-described genetic disorders, such as Down syndrome, which can include multiple congenital anomalies of the cardiac, central nervous and gastrointestinal systems [Solomon et al., 2010a
], mitochondropathies have been posited as disease modifier. Mitochondrial dysfunction due to mtDNA mutations, mitochondrial enzyme deficiencies leading to altered patterns of apoptosis and increased oxidative stress, has been reported as playing a role in the clinical manifestations of Down syndrome [Busciglio et al., 2002
; Busciglio, 2010
; Tiano and Busciglio, 2011
], for example, by affecting the frequency of diabetes mellitus and Alzheimer disease, altering the immune system, and contributing to neurological effects [Prince et al., 1994
; Bersu et al., 1998
; Druzhyna et al., 1998
; Schuchmann and Heinemann, 2000
; Conti et al., 2007
; Roat et al., 2007
In summary, we suggest that mitochondrial dysfunction should be considered when a patient presents with multiple congenital anomalies and clinical signs, and symptoms of mitochondrial involvement or related IEM. These clinical clues can include evidence for a maternal inheritance pattern, abnormal glycemic control, cyclic vomiting, developmental delay and other related signs of neurological disease, dysautonomia, intestinal malabsorption, pancreatic insufficiency, ptosis, episodic vomiting, and clinical response to ‘mitochondrial cocktail’ [Solomon et al., 2011
Finally, it must be admitted that past critiques have pointed out that mitochondrial defects have been the default explanation for many inexplicable conditions. Others believe that mitochondria may, however, play a unifying role in a large and underappreciated number of medically significant conditions. DiMauro 
has even called mitochondrial mutations a ‘Pandora's box’, perhaps reminding us of the difficulties in understanding and interpreting the many types of mitochondrial dysfunction and their potentially devastating consequences. At the same time, we must stride for means to discover new and better treatments for the many manifestations of mitochondrial disease. Despite the diversity of opinions, the bottom line is that much more research and critical evaluation is required in order to find answers for individuals affected by either or both VACTERL association and mitochondrial disease. This is especially important as some metabolic and mitochondrial disorders are amenable to certain types of treatment, and key avenues may emerge in the study of VACTERL association and related conditions related to mechanisms to ameliorate disease severity. As the causes of VACTERL association are discovered, it will be fascinating to look back in order to determine whether identified molecular etiologies do need point to a common path involving the mitochondria.