Marcinek Lab

Mitochondria and Muscle Aging Research

Mitochondrial Redox Biology
The Mito­chon­dr­ial Free Rad­i­cal The­ory of Aging (MFRTA) is not ade­quate to explain the effects of age and rever­sal of dys­func­tion. The focus on oxida­tive dam­age and free rad­i­cal scav­eng­ing in the analy­sis of MFRTA is not ade­quate to test the role of oxida­tive stress in aging. Our recent papers demon­strate a dynamic inter­ac­tion between oxi­dants and mito­chon­dr­ial ener­get­ics that 1) are depen­dent on the inter­ac­tion between the mito­chon­dria and cell envi­ron­ment, and 2) can­not be explained by the tra­di­tional view of oxida­tive dam­age. Cel­lu­lar oxi­dants play an impor­tant role in cell sig­nal­ing through their inter­ac­tion with the redox buffer­ing sys­tem and mod­i­fi­ca­tion of pro­tein thiol groups. This sys­tem, com­pris­ing the metabo­lites, GSH and NADPH and enzymes such as thiore­dox­ins, per­ox­ire­dox­ins, and glutare­dox­ins among oth­ers, exists in both the mito­chon­dria and cytoso­lic com­part­ments and is respon­si­ble for sens­ing and respond­ing to changes in the redox sta­tus of the cell. Com­mu­ni­ca­tion between the redox buffer­ing sys­tems and cel­lu­lar phys­i­ol­ogy pri­mar­ily occurs through reversible post-translational mod­i­fi­ca­tions of pro­tein thi­ols, includ­ing S-glutathionylation (PSSG), sulfeny­la­tion, and S-nitrosylation. One area of focus of our research is attempt­ing to under­stand the inter­ac­tion mito­chon­dr­ial func­tion, redox biol­ogy, and the thiol pro­teome in health and disease.

Skele­tal Mus­cle Aging
Improv­ing skele­tal mus­cle func­tion with age would have a sig­nif­i­cant impact on qual­ity of life in the elderly. Sar­cope­nia is the age-related loss of mus­cle con­trac­til­ity as well as mus­cle atro­phy. This loss of both qual­ity and quan­tity of mus­cle is an impor­tant pub­lic health con­cern due to its role in increased mor­bid­ity and nurs­ing home place­ment. Poor mus­cle func­tion is asso­ci­ated with exer­cise intol­er­ance and fatigue, which lead to poor qual­ity of life, loss of inde­pen­dence, and age-related dis­eases. This loss of inde­pen­dence is due to an inabil­ity to per­form activ­i­ties of daily liv­ing that require sus­tained mus­cle power, such as walk­ing, dress­ing, and show­er­ing as well as increased risk of falling. The result­ing increased rates of nurs­ing home place­ment and hos­pi­tal­iza­tion make the loss of skele­tal mus­cle func­tion with age a grow­ing pub­lic health cri­sis in terms of both qual­ity of life and eco­nomic costs to soci­ety. Janssen et al. esti­mated these costs at $18 bil­lion dol­lars in 2001 and pre­dicted that a 10% reduc­tion in sar­cope­nia preva­lence would lead to a sav­ings of $1.4 bil­lion in health­care costs (adjusted to 2010 dol­lars). Despite this, there are few treat­ment options to reverse mus­cle degen­er­a­tion in the elderly due in large part to the poor under­stand­ing of the mech­a­nisms that under­lie this dys­func­tion. A major inter­est in our lab is iden­ti­fy­ing new inter­ven­tions that have the poten­tial to trans­late into elderly patients to improve mus­cle func­tion and qual­ity of life.

Mito­chon­dria and Xenobiotics
Mito­chon­dr­ial func­tion is involved in the tox­i­c­ity of many xeno­bi­otic com­pounds (chem­i­cal com­pounds for­eign to a liv­ing organ­ism). We are increas­ingly exposed to a vari­ety of xeno­bi­otic com­pounds such as drugs, envi­ron­men­tal pol­lu­tants, and even nat­u­rally pro­duced tox­ins. The tox­i­c­ity of many of these com­pounds involves either direct or sec­ondary effects on mito­chon­dr­ial func­tion. Exam­ples of direct effects include inhi­bi­tion of elec­tron trans­port sys­tem com­po­nents that can dis­rupt energy pro­duc­tion and lead to oxida­tive stress. Indi­rect effects can occur through stim­u­la­tion of non-mitochondrial oxida­tive stress that then results in impaired mito­chon­dr­ial func­tion and ampli­fi­ca­tion of the tox­i­c­ity. The acute tox­i­c­ity effects of high dose expo­sures of many com­pounds are well estab­lished. How­ever, the mech­a­nisms by which chronic expo­sure dis­rupts cell and organ­is­mal func­tion and con­tributes to last­ing dys­func­tion are less well known. Our lab is par­tic­u­larly inter­ested in the inter­ac­tion between mito­chon­dr­ial biol­ogy, chronic xeno­bi­otic expo­sure, and dis­ease. We are pur­su­ing this area in col­lab­o­ra­tion with tox­i­col­o­gists and clin­i­cal scientists.