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Using the conditional <jats:italic>Fxn<\/jats:italic><jats:sup>flox\/null<\/jats:sup>::MCK-Cre knock-out (<jats:italic>Fxn<\/jats:italic>-cKO) mouse model, we discovered significant sex differences in the progression towards heart failure, with <jats:italic>Fxn<\/jats:italic>-cKO males exhibiting a worse cardiac phenotype, low survival rate, kidney and reproductive organ deficiencies. These differences are likely due to a decline in testosterone in <jats:italic>Fxn<\/jats:italic>-cKO males. The decrease in testosterone was related to decreased expression of proteins involved in cholesterol transfer into the mitochondria: StAR and TSPO on the outer mitochondrial membrane, and the cholesterol side-chain cleavage enzyme P450scc and ferredoxin on the inner mitochondrial membrane. Expression of excitation-contraction coupling proteins (L-type calcium channel, RyR2, SERCA2, phospholamban and CaMKII\u03b4) was decreased significantly more in <jats:italic>Fxn<\/jats:italic>-cKO males. 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