In animal cells, mitochondria are semiautonomous organelles of virtually "hostile" (bacterial) origin, with their own code and genome (mtDNA). The semiautonomy and restricted resources could result in occasional "conflicts of interests" with other cellular components, in which mitochondria have greater chances to be "the weakest link," thus limiting longevity. Two principal questions are addressed: (1) to what extent the mammalian maximum life span (MLS) is associated with mtDNA base composition? (2) Does mtDNA base composition correlate with another important mitochondria-associated variable-resting metabolic rate (RMR)-and whether they complement each other in determination of MLS? Analysis of 140 mammalian species revealed significant correlations between MLS and the content of the four mtDNA nucleotides, especially noted for GC pairs (r(2) = 0.42; p < 10(-17)). The most remarkable finding of this study is that multivariate stepwise analysis selected only the GC content and RMR, which together explained 77% of variation in MLS (p < 10(-25)). To the authors' knowledge, it is the highest coefficient of MLS determination that has ever been reported for a comparable sample size. Taking into account substantial errors in estimation of MLS and RMR, it could mean that the GC and RMR explain most of the MLS biological variation. Other putative players in MLS determination should have relatively small contribution or their effects should be realized via the same channels. Although further research is clearly warranted, the extraordinary high correlation of mtDNA GC and RMR with MLS suggests a "direct hitting" of the core longevity targets, inferring mitochondria as a primary object for longevity-promoting interventions.