Amino acid replacement: G116E.
Nucleotide substitution: G?A.
Until late life, daily activity of mt:ATPase61 flies is significantly reduced while nightly activity is unaltered; in late life, daily activity becomes unaltered while nightly activity becomes significantly reduced compared to controls. In young mutants both relative amount of total sleep and bout length are increased while in old mutants both are significantly reduced compared to controls.
At different stages of life, mt:ATPase61 adults exhibit alterations in averaged sleep values at multiple time points when compared to controls.
Under constant darkness young mt:ATPase61 flies are more arrhythmic while neither the circadian period length nor the rhythm strength is significantly different than controls. Later in life, in addition to a drastic increase in the number of arrhythmic mutant flies, the circadian period length and rhythm strength are significantly reduced compared to controls.
Eclosion of mt:ATPase61 flies occur significantly less during the expected ZT 0-4 window and significantly more in the middle of the day (ZT4-8) and overnight (ZT12-24) when compared to controls.
In old mt:ATPase61 flies, the large lateral ventral neurons do not show the decrease in firing frequency from morning to afternoon observed in controls.
Old mt:ATPase61 flies are significantly more awakened by mild mechanical stimulation in ZT8-10 than controls; although awake mutant and control flies show an increase in activity upon mild and moderate mechanical stimulation, mutants still show increased activity upon strong stimulation, whereas controls exhibit a 'freezing' response.
Mutant flies are morphologically and behaviourally normal at eclosion, but begin to have reduced locomotor activity at approximately 8 days o age. By day 13, they are sensitive to mechanical stress (resulting in paralysis). At approximately 20 days of age, sporadic and unprovoked seizure-like activity is seen. The phenotypes continue to worsen with age, before the flies die prematurely.
The mutant animals show modestly elevated respiration during the period where no mutant phenotypes are seen. The onset of mutant phenotypes is associated with a striking increase in respiration followed by a dramatic drop in respiration corresponding to severe phenotypic impairment.
Aged mutant adults show seizure-like convulsions following exposure to strobe lighting at 25 days of age, but this phenotype is not seen in younger mutant flies (5, 13 or 20 days of age). The convulsive behaviour seen in the 25 day old mutants is followed by full paralysis that continues well after the resumption of normal lighting.
Mutant animals show a similar developmental survival rate to adulthood as wild-type controls at 22[o]C and 29[o]C. The mutants show a modest but significant shortening in the time of development during larval and pupal stages at 22[o]C and during the larval stage at 29[o]C. Mutant females lay significantly more eggs than wild-type controls during their first week of life.
mt:ATPase61 mutants exhibit shortened lifespan, muscle degeneration, mitochondrial dysfunction, stress sensitivity, progressive neural dysfunction, profound ultrastructural impairment of the mitochondria, and severely reduced mitochondrial ATP synthase activity.
mt:ATPase61 animals transmit conditional paralysis and reduced lifespan (with 100%) penetrance to their offspring when maternal inheritance is maintained.
mt:ATPase61 mutants exhibit a significant reduction in lifespan compared to wild-type controls, with a median lifespan of 12 days compared to 50 days.
Aged mt:ATPase61 mutants do not exhibit any apparent histologic abnormalities. Young animals are free of pathology, demonstrating that the neurodegeneration is strictly progressive.
Muscle degeneration in the dorsal flight muscles of mt:ATPase61 mutants is strictly progressive. Young animals reveal no evidence of myopathology. At day 10 mt:ATPase61 mutants reveal a striking pathology, consistent with the onset of poor viability. Day 5 mt:ATPase61 mutants have less severe myopathology.
mt:ATPase61 mutants exhibit some evidence of thoracic ganglion neurodegeneration, namely individual large vacuolar structures that are not observed in age-matched animals.
mt:ATPase61 mutans have reduced locomotor function and conditional paralysis brought on by mechanical stress.
mt:ATPase61 mutants exhibit a markedly progressive paralysis phenotype brought on by mechanical stress. Young mutants, day 2 and 4, are not more affected by mechanical stress than wild-type, although there is greater variability in recovery time in the mutants than age-matched wild-type animals. However, by day 6, mt:ATPase61 mutants demonstrate significant locomotor impairment.
TEM analysis of mt:ATPase61 mutants reveal mitochondria displaying highly abnormal internal compartmentalisation that is not typical in age-matched wild-type flies. The numerous small, round cristae (~50-80nm in diameter) give the mitochondria a honeycomb appearance. The vast majority of mitochondria in midbrain micrographs from mt:ATPase61 animals have abnormal internal membrane morphology. The round inner membrane compartments are part of a highly interconnected membrane network. The tightly packed spherical compartments are connected by narrow tubular junctions to each other and to the inner boundary membrane (i.e., the region that parallels the outer membrane). The roughly spherical compartments are clearly contiguous with the lamella regions of the inner membrane. At numerous places the lamellar membranes appear to be fenestrated. Although mitochondria are morphologically abnormal, the density (number of mitochondria per unit area) of mitochondria in mt:ATPase61 mutants is not significantly different from that of wild-type control animals.
The rates of respiration of mt:ATPase61 and age-matched wild-type control populations are indistinguishable.
There are no significant differences between the resting meotabolic rate of individual mt:ATPase61 and age-matched wild-type control flies.
short lived locomotor behaviour defective muscle system mt:ATPase61 mutants show myodegeneration.
mt:ATPase61 has short lived phenotype, enhanceable by sesB1
mt:ATPase61 has abnormal locomotor behavior phenotype, enhanceable by sesB1
mt:ATPase61 has abnormal neuroanatomy phenotype, enhanceable by sesB1
mt:ATPase61 is an enhancer of short lived phenotype of sesB1
mt:ATPase61 is an enhancer of abnormal locomotor behavior phenotype of sesB1
mt:ATPase61 is an enhancer of abnormal neuroanatomy phenotype of sesB1
mt:ATPase61 is an enhancer of adult ventral nerve cord phenotype of sesB1
The lifespan of sesB1; mt:ATPase61 double mutants reveals an additional impairment of adult viability beyond each of the individual mitochondrial mutants. It is important to note that mt:ATPase61 does not appear to compensate for the sesB1 mutation and improve viability.
Severe neuropathology is observed in aged sesB1; mt:ATPase61 double mutant brains, namely individual large vacuolar structures that are not observed in age-matched animals. Young animals are free of pathology, demonstrating that the neurodegeneration is strictly progressive.
The mt:ATPase61 mutant accelerates the sesB1 degeneration of the thoracic ganglion.
sesB1; mt:ATPase61 double mutants reveal enhanced locomotor impairment with an earlier onset than either of the separate mitochondrial mutants.
